Compounds and methods for kinase modulation, and indications therefor

ABSTRACT

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

This application is a continuation application of U.S. application Ser.No. 15/656,990, filed Jul. 21, 2017, which is a continuation of U.S.application Ser. No. 15/260,042, filed Sep. 8, 2016, now U.S. Pat. No.9,884,539, which is a continuation application of U.S. application Ser.No. 15/048,851, filed Feb. 19, 2016, now U.S. Pat. No. 9,469,640, whichis a continuation of U.S. application Ser. No. 13/926,959, filed Jun.25, 2013, which is a continuation of U.S. application Ser. No.13/866,353, filed Apr. 19, 2013, which is a continuation application ofSer. No. 12/669,450, filed Jan. 15, 2010, which application is aNational Phase application under 35 U.S.C. § 371 of PCT/US2008/070124,filed Jul. 16, 2008, which claims the benefit under 35 U.S.C. § 119(e)from U.S. Application No. 60/959,907, filed Jul. 17, 2007, whichapplications are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION Background of the Invention

The present invention relates to kinases and compounds which modulatekinases, and uses therefor. Particular embodiments contemplate diseaseindications which are amenable to treatment by modulation of kinaseactivity by the compounds of the present invention.

SUMMARY OF THE INVENTION

Compounds are contemplated that are active on protein kinases ingeneral, including, but not limited to, Abl, Akt1, Akt2, Akt3, ALK,Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1,Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3,FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2,Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2,Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1,MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta,PKC theta, Plk1, Pyk2, Ret, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC,Tie2, TrkA, TrkB, Yes, and/or Zap70, including any mutations of thesekinases. In some aspects, the compounds are active on Raf proteinkinases including A-Raf, B-Raf and/or c-Raf-1, including any mutationsthereof. In some aspects, compounds are of Formula I as described below.

Also contemplated in accordance with the present invention are methodsfor the use of the above-described compounds in treating diseases andconditions associated with regulation of the activity of theabove-described kinases. Thus, the use of compounds for therapeuticmethods involving modulation of protein kinases are provided, as well ascompounds that can be used for therapeutic methods involving modulationof protein kinases.

In some embodiments, compounds have the structure according to thefollowing Formula I:

or a salt, a prodrug, a tautomer or an isomer thereof,wherein:

-   -   Ar is optionally substituted heteroaryl;    -   R¹ at each occurrence is independently selected from the group        consisting of halogen, optionally substituted lower alkyl,        optionally substituted lower alkenyl, optionally substituted        lower alkynyl, optionally substituted cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl, —NR₂, —CN, —O—R⁵, —N(R⁵)—R⁶,        —C(X)—N(R⁵)—R⁶, —C(X)—R⁷, —S(O)₂—N(R⁵)—R⁶, —S(O)_(n)—R⁷,        —O—C(X)—R⁷, —C(X)—O—R⁵, —C(NH)—N(R⁸)—R⁹, —N(R⁵)—C(X)—R⁷,        —N(R⁵)—S(O)₂—R⁷, —N(R⁵)—C(X)—N(R⁵)—R⁶, and        —N(R⁵)—S(O)₂—N(R⁵)—R⁶;    -   m is 0, 1, 2, 3, 4 or 5;    -   n is 0, 1 or 2;    -   R² is hydrogen, lower alkyl or halogen;    -   L₂ is selected from the group consisting of —S(O)₂—, —C(X)—,        —C(X)—N(R¹⁰)—, and —S(O)₂—N(R¹⁰)—;    -   R³ is optionally substituted lower alkyl, optionally substituted        C₃₋₆ cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl or optionally substituted        heteroaryl;    -   L₁ is selected from the group consisting of a bond, —N(R¹¹)—,        —O—, —S—, —C(X)—, —C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—,        —C(R¹²R¹³)—N(R¹¹)—, —N(R¹¹)—C(R¹²R¹³)—, —O—C(X)—, —C(X)—O—,        —C(X)—N(R¹¹)—, —N(R¹¹)—C(X)—, —S(O)—, —S(O)₂—, —S(O)₂—N(R¹¹)—,        —N(R¹¹)—S(O)₂—, —C(NH)—N(R¹¹)—, —N(R¹¹)—C(NH)—,        —N(R¹¹)—C(X)—N(R¹¹)—, and —N(R¹¹)—S(O)₂—N(R¹¹)—;    -   X is O or S;    -   R⁴, R¹⁰ and each R¹¹ are independently hydrogen or lower alkyl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, —OH,        —NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        fluoro substituted mono-alkylamino, di-alkylamino, fluoro        substituted di-alkylamino, and —NR¹⁴R¹⁵;    -   R⁵, R⁶, R⁸, and R⁹ at each occurrence are independently selected        from the group consisting of hydrogen, optionally substituted        lower alkyl, optionally substituted C₃₋₆ alkenyl, optionally        substituted C₃₋₆ alkynyl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl, and optionally substituted heteroaryl, or    -   R⁸ and R⁹ combine with the nitrogen to which they are attached        to form a 5-7 membered optionally substituted nitrogen        containing heterocycloalkyl or a 5 or 7 membered optionally        substituted nitrogen containing heteroaryl;    -   R⁷ at each occurrence is independently selected from the group        consisting of optionally substituted lower alkyl, optionally        substituted C₃₋₆ alkenyl, optionally substituted C₃₋₆ alkynyl,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, and optionally        substituted heteroaryl;    -   R¹² and R¹³ are independently selected from the group consisting        of hydrogen, fluoro, —OH, —NH₂, lower alkyl, lower alkoxy, lower        alklylthio, mono-alkylamino, di-alkylamino, and —NR¹⁴R¹⁵,        wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower        alkylthio, mono-alkylamino, or di-alkylamino are optionally        substituted with one or more substituents selected from the        group consisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino; or    -   R¹² and R¹³ combine with the carbon to which they are attached        to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered        monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl        or monocyclic heterocycloalkyl are optionally substituted with        one or more substituents selected from the group consisting of        halogen, —OH, —NH₂, lower alkyl, fluoro substituted lower alkyl,        lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,        fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino; and    -   R¹⁴ and R¹⁵ at each occurrence independently combine with the        nitrogen to which they are attached to form a 5-7 membered        heterocycloalkyl or 5-7 membered heterocycloalkyl substituted        with one or more substituents selected from the group consisting        of fluoro, —OH, —NH₂, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, and fluoro substituted lower alkylthio,        provided, however, that when L₁ is a bond, —NR¹¹—, —O—, —S—,        —C(X)—, —S(O)—, or —S(O)₂—, Ar is not        1H-pyrrolo[2,3-b]pyridine-3-yl, 1H-pyrazolo[3,4-b]pyridine-3-yl,        5H-pyrrolo[2,3-b]pyrazine-7-yl,        7H-pyrrolo[2,3-d]pyrimidine-5-yl, or        7H-pyrrolo[2,3-c]pyridazine-5-yl, i.e. is not

wherein

indicates the attachment point to L₁.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ia:

or a salt, a prodrug, a tautomer or an isomer thereof,wherein m, Ar, R¹, R², R³, R⁴, and L₁ are as defined for Formula I.

In some embodiments of compounds of Formula I or Ia, L₁ is a bond,—N(R¹¹)—, —N(R¹¹)—C(X)—, —N(R¹¹)—S(O)₂—, —N(R¹¹)—C(NH)—,—N(R¹¹)—C(X)—N(R¹¹)—, or —N(R¹¹)—S(O)₂—N(R¹¹)—, also —N(R¹¹)—,—N(R¹¹)—C(X)—, or —N(R¹¹)—S(O)₂—, also —N(R¹¹)—C(O)—, wherein the leftside (i.e. —N(R¹¹)—) of L₁ is attached to Ar and the right side of L₁ isattached to the phenyl ring of Formula I or Ia. In some embodiments, L₁is a bond, —N(R¹¹)—, —N(R¹¹)—C(X)—, —N(R¹¹)—S(O)₂—, —N(R¹¹)—C(NH)—,—N(R¹¹)—C(X)—N(R¹¹)—, or —N(R¹¹)—S(O)₂—N(R¹¹)—, also —N(R¹¹)—,—N(R¹¹)—C(X)—, or —N(R¹¹)—S(O)₂—, also —N(R¹¹)—C(O)—, and each R¹¹ andR⁴ are independently hydrogen or lower alkyl, wherein lower alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of fluoro, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, and fluoro substituted lower alkylthio,preferably each R¹¹ and R⁴ are H.

In some embodiments of compounds of Formula I or Ia, L₁ is—C(X)—N(R¹¹)—, —C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or—N(R¹¹)—C(R¹²R¹³)—, wherein the left side of L₁ is attached to Ar andthe right side of L₁ is attached to the phenyl ring of Formula I or Ia.In some embodiments, L₁ is —C(X)—N(R¹¹)—, —C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—,—C(R¹²R¹³)—N(R¹¹)—, or —N(R¹¹)—C(R¹²R¹³)—, and each R¹¹ and R⁴ areindependently hydrogen or lower alkyl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, and fluoro substituted lower alkylthio, preferably eachR¹¹ and R⁴ are H.

In some embodiments of compounds of Formula I or Ia, R² is hydrogen,fluoro or chloro, preferably fluoro or chloro. In some embodiments, R²is hydrogen, fluoro or chloro, each R¹¹ and R⁴ are independentlyhydrogen or lower alkyl, wherein lower alkyl is optionally substitutedwith one or more substituents selected from the group consisting offluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,and fluoro substituted lower alkylthio, preferably R² is fluoro orchloro and each R¹¹ and R⁴ are H. In some embodiments, R² is hydrogen,fluoro or chloro, preferably fluoro or chloro, and L₁ is a bond,—N(R¹¹)—, —N(R¹¹)—C(X)—, —N(R¹¹)—S(O)₂—, —N(R¹¹)—C(NH)—,—N(R¹¹)—C(X)—N(R¹¹)—, or —N(R¹¹)—S(O)₂—N(R¹¹)—, also —N(R¹¹)—,—N(R¹¹)—C(X)—, or —N(R¹¹)—S(O)₂—, also —N(R¹¹)—C(O)—, wherein the leftside (i.e. —N(R¹¹)—) of L₁ is attached to Ar and the right side of L₁ isattached to the phenyl ring of Formula I or Ia. In some embodiments, R²is hydrogen, fluoro or chloro, preferably fluoro or chloro; L₁ is abond, —N(R¹¹)—, —N(R¹¹)—C(X)—, —N(R¹¹)—S(O)₂—, —N(R¹¹)—C(NH)—,—N(R¹¹)—C(X)—N(R¹¹)—, or —N(R¹¹)—S(O)₂—N(R¹¹)—, also —N(R¹¹)—,—N(R¹)—C(X)—, or —N(R¹¹)—S(O)₂—, also —N(R¹¹)—C(O)—; and each R¹¹ and R⁴are independently hydrogen or lower alkyl, wherein lower alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of fluoro, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, and fluoro substituted lower alkylthio,preferably each R¹¹ and R⁴ are H.

In some embodiments of compounds of Formula I or Ia, R² is hydrogen,fluoro or chloro, preferably fluoro or chloro. In some embodiments, R²is hydrogen, fluoro or chloro, each R¹¹ and R⁴ are independentlyhydrogen or lower alkyl, wherein lower alkyl is optionally substitutedwith one or more substituents selected from the group consisting offluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,and fluoro substituted lower alkylthio, preferably R² is fluoro orchloro and each R¹¹ and R⁴ are H. In some embodiments, R² is hydrogen,fluoro or chloro, preferably fluoro or chloro, and L₁ is —C(X)—N(R¹¹)—,—C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or —N(R¹¹)—C(R¹²R¹³)—,wherein the left side of L₁ is attached to Ar and the right side of L₁is attached to the phenyl ring of Formula I or Ia. In some embodiments,R² is hydrogen, fluoro or chloro, preferably fluoro or chloro; L₁ is—C(X)—N(R¹¹)—, —C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or—N(R¹¹)—C(R¹²R¹³)—; and each R¹¹ and R⁴ are independently hydrogen orlower alkyl, wherein lower alkyl is optionally substituted with one ormore substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably each R¹¹ and R⁴ are H.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ib:

or a salt, a prodrug, a tautomer or an isomer thereof,wherein A is —C(O)— or —C(R¹²R¹³)—; andm, Ar, R¹, R², R³, R⁴, R¹¹, R¹² and R¹³ are as defined for Formula I.

In some embodiments of compounds of Formula Ib, R⁴, R¹¹, R¹² and R¹³ areindependently hydrogen or lower alkyl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, and fluoro substituted lower alkylthio, preferably R⁴,R¹¹, R¹² and R¹³ are H. In some embodiments, R² is hydrogen, fluoro orchloro, preferably fluoro or chloro. In some embodiments, R² ishydrogen, fluoro or chloro, and R⁴, R¹¹, R¹² and R¹³ are independentlyhydrogen or lower alkyl, wherein lower alkyl is optionally substitutedwith one or more substituents selected from the group consisting offluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,and fluoro substituted lower alkylthio, preferably R² is fluoro orchloro and R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments of compounds of Formula Ib, A is —C(O)—, and R⁴ andR¹¹ are independently hydrogen or lower alkyl, wherein lower alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of fluoro, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, and fluoro substituted lower alkylthio,preferably R⁴ and R¹¹ are H. In some embodiments, A is —C(O)—, and R² ishydrogen, fluoro or chloro, preferably fluoro or chloro. In someembodiments, A is —C(O)—, R² is hydrogen, fluoro or chloro, preferablyfluoro or chloro; and R⁴ and R¹¹ are independently hydrogen or loweralkyl, wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R⁴ and R¹¹ are H.

In some embodiments of compounds of Formula Ib, A is —C(R¹²R¹³)—, andR⁴, R¹¹, R¹² and R¹³ are independently hydrogen or lower alkyl, whereinlower alkyl is optionally substituted with one or more substituentsselected from the group consisting of fluoro, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, and fluoro substituted loweralkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H. In some embodiments, Ais —C(R¹²R¹³)—, R¹² and R¹³ are independently hydrogen or lower alkyl,wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R¹² and R¹³ are H, and R² is hydrogen,fluoro or chloro, preferably fluoro or chloro. In some embodiments, A is—C(R¹²R¹³)—; R² is hydrogen, fluoro or chloro, preferably fluoro orchloro; and R⁴, R¹¹, R¹² and R¹³ are independently hydrogen or loweralkyl, wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ic:

or a salt, a prodrug, a tautomer or an isomer thereof,wherein m, Ar, R¹, R², R³, and R⁴, are as defined for Formula I.

In some embodiments of compounds of Formula Ic, R⁴ is hydrogen or loweralkyl, wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R⁴ is H. In some embodiments, R² ishydrogen, fluoro or chloro, preferably fluoro or chloro. In someembodiments, R² is hydrogen, fluoro or chloro and R⁴ is hydrogen orlower alkyl, wherein lower alkyl is optionally substituted with one ormore substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably R² is fluoro or chloro and R⁴ isH.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Id:

or a salt, a prodrug, a tautomer or an isomer thereof,wherein A is —C(O)— or —C(R¹²R¹³)—; andm, Ar, R¹, R², R³, R⁴, R¹¹, R¹², R¹³ and L₂ are as defined for FormulaI.

In some embodiments of compounds of Formula Id, R⁴, R¹¹, R¹² and R¹³ areindependently hydrogen or lower alkyl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, and fluoro substituted lower alkylthio, preferably R⁴,R¹¹, R¹² and R¹³ are H. In some embodiments, R² is hydrogen, fluoro orchloro, preferably fluoro or chloro. In some embodiments, R² ishydrogen, fluoro or chloro, and R⁴, R¹¹, R¹² and R¹³ are independentlyhydrogen or lower alkyl, wherein lower alkyl is optionally substitutedwith one or more substituents selected from the group consisting offluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,and fluoro substituted lower alkylthio, preferably R² is fluoro orchloro and R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments of compounds of Formula Id, A is —C(O)—, and R⁴ andR¹¹ are independently hydrogen or lower alkyl, wherein lower alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of fluoro, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, and fluoro substituted lower alkylthio,preferably R⁴ and R¹¹ are H. In some embodiments, A is —C(O)—, and R² ishydrogen, fluoro or chloro, preferably fluoro or chloro. In someembodiments, A is —C(O)—, R² is hydrogen, fluoro or chloro, preferablyfluoro or chloro; and R⁴ and R¹¹ are hydrogen or lower alkyl, whereinlower alkyl is optionally substituted with one or more substituentsselected from the group consisting of fluoro, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, and fluoro substituted loweralkylthio, preferably R⁴ and R¹¹ are H.

In some embodiments of compounds of Formula Id, A is —C(R¹²R¹³)—, andR⁴, R¹¹, R¹² and R¹³ are independently hydrogen or lower alkyl, whereinlower alkyl is optionally substituted with one or more substituentsselected from the group consisting of fluoro, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, and fluoro substituted loweralkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H. In some embodiments, Ais —C(R¹²R¹³)—, R¹² and R¹³ are independently hydrogen or lower alkyl,wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R¹² and R¹³ are H, and R² is hydrogen,fluoro or chloro, preferably fluoro or chloro. In some embodiments, A is—C(R¹²R¹³)—; R² is hydrogen, fluoro or chloro, preferably fluoro orchloro; and R⁴, R¹¹, R¹² and R¹³ are independently hydrogen or loweralkyl, wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ie:

or a salt, a prodrug, a tautomer or an isomer thereof,wherein m, Ar, R¹, R², R³, R⁴, and L₂ are as defined for Formula I.

In some embodiments of compounds of Formula Ie, R⁴ is hydrogen or loweralkyl, wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R⁴ is H. In some embodiments, R² ishydrogen, fluoro or chloro, preferably fluoro or chloro. In someembodiments, R² is hydrogen, fluoro or chloro and R⁴ is hydrogen orlower alkyl, wherein lower alkyl is optionally substituted with one ormore substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably R² is fluoro or chloro and R⁴ isH.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula If:

or a salt, a prodrug, a tautomer or an isomer thereof,

wherein:

L₃ is —C(X)—N(R¹¹)—, —C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—,or —N(R¹¹)—C(R¹²R¹³)—; and

m, Ar, R¹, R², R³, R⁴, R¹¹, R¹², R¹³, and X are as defined for FormulaI.

In some embodiments of compounds of Formula If, L₃ is —C(O)—N(R¹¹)—,—C(R¹²R¹³)—O—, —O—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or —N(R¹¹)—C(R¹²R¹³)—,wherein the left side of L₃ is attached to Ar and the right side of L₃is attached to the phenyl ring of Formula If. In some embodiments, L₃ is—C(O)—N(R¹¹)—, —C(R¹²R¹³)—O—, —O—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or—N(R¹¹)—C(R¹²R¹³)—, and R⁴, R¹¹, R¹² and R¹³ are independently hydrogenor lower alkyl, wherein lower alkyl is optionally substituted with oneor more substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ig:

or a salt, a prodrug, a tautomer or an isomer thereof,

wherein:

L₃ is —C(X)—N(R¹¹)—, —C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—,or —N(R¹¹)—C(R¹²R¹³)—; and

m, Ar, R¹, R², R³, R⁴, R¹¹, R¹², R¹³, X and L₂ are as defined forFormula I.

In some embodiments of compounds of Formula Ig, L₃ is —C(O)—N(R¹¹)—,—C(R¹²R¹³)—O—, —O—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or —N(R¹¹)—C(R¹²R¹³)—,wherein the left side of L₃ is attached to Ar and the right side of L₃is attached to the phenyl ring of Formula Ig. In some embodiments, L₃ is—C(O)—N(R¹¹)—, —C(R¹²R¹³)—O—, —O—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or—N(R¹¹)—C(R¹²R¹³)—, and R⁴, R¹¹, R¹² and R¹³ are independently hydrogenor lower alkyl, wherein lower alkyl is optionally substituted with oneor more substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ih:

or a salt, a prodrug, a tautomer or an isomer thereof,wherein A is —C(O)— or —C(R¹²R¹³)—; andm, Ar, R¹, R², R³, R⁴, R¹¹, R¹² and R¹³ are as defined for Formula I.

In some embodiments of compounds of Formula Ih, R⁴, R¹¹, R¹² and R¹³ areindependently hydrogen or lower alkyl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, and fluoro substituted lower alkylthio, preferably R⁴,R¹¹, R¹² and R¹³ are H. In some embodiments, R² is hydrogen, fluoro orchloro, preferably fluoro or chloro. In some embodiments, R² ishydrogen, fluoro or chloro, and R⁴, R¹¹, R¹² and R¹³ are independentlyhydrogen or lower alkyl, wherein lower alkyl is optionally substitutedwith one or more substituents selected from the group consisting offluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,and fluoro substituted lower alkylthio, preferably R² is fluoro orchloro and R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments of compounds of Formula Ih, A is —C(O)—, and R⁴ andR¹¹ are independently hydrogen or lower alkyl, wherein lower alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of fluoro, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, and fluoro substituted lower alkylthio,preferably R⁴ and R¹¹ are H. In some embodiments, A is —C(O)—, and R² ishydrogen, fluoro or chloro, preferably fluoro or chloro. In someembodiments, A is —C(O)—, R² is hydrogen, fluoro or chloro, preferablyfluoro or chloro; and R⁴ and R¹¹ are independently hydrogen or loweralkyl, wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R⁴ and R¹¹ are H.

In some embodiments of compounds of Formula Ih, A is —C(R¹²R¹³)—, andR⁴, R¹¹, R¹² and R¹³ are independently hydrogen or lower alkyl, whereinlower alkyl is optionally substituted with one or more substituentsselected from the group consisting of fluoro, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, and fluoro substituted loweralkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H. In some embodiments, Ais —C(R¹²R¹³)—, R¹² and R¹³ are independently hydrogen or lower alkyl,wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R¹² and R¹³ are H, and R² is hydrogen,fluoro or chloro, preferably fluoro or chloro. In some embodiments, A is—C(R¹²R¹³)—; R² is hydrogen, fluoro or chloro, preferably fluoro orchloro; and R⁴, R¹¹, R¹² and R¹³ are independently hydrogen or loweralkyl, wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ii:

or a salt, a prodrug, a tautomer or an isomer thereof,wherein A is —C(O)— or —C(R¹²R¹³)—; andm, Ar, R¹, R², R³, R⁴, R¹¹, R¹², R¹³ and L₂ are as defined for FormulaI.

In some embodiments of compounds of Formula Ii, R⁴, R¹¹, R¹² and R¹³ areindependently hydrogen or lower alkyl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, and fluoro substituted lower alkylthio, preferably R⁴,R¹¹, R¹² and R¹³ are H. In some embodiments, R² is hydrogen, fluoro orchloro, preferably fluoro or chloro. In some embodiments, R² ishydrogen, fluoro or chloro, and R⁴, R¹¹, R¹² and R¹³ are independentlyhydrogen or lower alkyl, wherein lower alkyl is optionally substitutedwith one or more substituents selected from the group consisting offluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,and fluoro substituted lower alkylthio, preferably R² is fluoro orchloro and R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments of compounds of Formula Ii, A is —C(O)—, and R⁴ andR¹¹ are independently hydrogen or lower alkyl, wherein lower alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of fluoro, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, and fluoro substituted lower alkylthio,preferably R⁴ and R¹¹ are H. In some embodiments, A is —C(O)—, and R² ishydrogen, fluoro or chloro, preferably fluoro or chloro. In someembodiments, A is —C(O)—, R² is hydrogen, fluoro or chloro, preferablyfluoro or chloro; and R⁴ and R¹¹ are hydrogen or lower alkyl, whereinlower alkyl is optionally substituted with one or more substituentsselected from the group consisting of fluoro, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, and fluoro substituted loweralkylthio, preferably R⁴ and R¹¹ are H.

In some embodiments of compounds of Formula Ii, A is —C(R¹²R¹³)—, andR⁴, R¹¹, R¹² and R¹³ are independently hydrogen or lower alkyl, whereinlower alkyl is optionally substituted with one or more substituentsselected from the group consisting of fluoro, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, and fluoro substituted loweralkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H. In some embodiments, Ais —C(R¹²R¹³)—, R¹² and R¹³ are independently hydrogen or lower alkyl,wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R¹² and R¹³ are H, and R² is hydrogen,fluoro or chloro, preferably fluoro or chloro. In some embodiments, A is—C(R¹²R¹³)—; R² is hydrogen, fluoro or chloro, preferably fluoro orchloro; and R⁴, R¹¹, R¹² and R¹³ are independently hydrogen or loweralkyl, wherein lower alkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio, preferably R⁴, R¹¹, R¹² and R¹³ are H.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ij:

or a salt, a prodrug, a tautomer or an isomer thereof,wherein:

-   -   m, Ar, R¹, R², R⁴, and L₁ are as defined for Formula I; and    -   R²² is selected from the group consisting of mono-alkylamino,        di-alkylamino, optionally substituted lower alkyl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl and optionally substituted        heteroaryl, wherein the alkyl chain(s) of mono-alkylamino or        di-alkylamino are independently optionally substituted with one        or more substituents selected from the group consisting of        fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino and cycloalkylamino.

In some embodiments of compounds of Formula Ij, L₁ is a bond, —N(R¹¹)—,—N(R¹¹)—C(X)—, —N(R¹¹)—S(O)₂—, —N(R¹¹)—C(NH)—, —N(R¹¹)—C(X)—N(R¹¹)—, or—N(R¹¹)—S(O)₂—N(R¹¹)—, also —N(R¹¹)—, —N(R¹¹)—C(X)—, or —N(R¹¹)—S(O)₂—,also —N(R¹¹)—C(O)—, wherein the left side (i.e. —N(R¹¹)—) of L₁ isattached to Ar and the right side of L₁ is attached to the phenyl ringof Formula Ij. In some embodiments, L₁ is a bond, —N(R¹)—, —N(R¹)—C(X)—,—N(R¹¹)—S(O)₂—, —N(R¹¹)—C(NH)—, —N(R¹¹)—C(X)—N(R¹¹)—, or—N(R¹¹)—S(O)₂—N(R¹¹)—, also —N(R¹¹)—, —N(R¹¹)—C(X)—, or —N(R¹¹)—S(O)₂—,also —N(R¹¹)—C(O)—, and each R¹¹ and R⁴ are independently hydrogen orlower alkyl, wherein lower alkyl is optionally substituted with one ormore substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably each R¹¹ and R⁴ are H.

In some embodiments of compounds of Formula Ij, L₁ is —C(X)—N(R¹¹)—,—C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or —N(R¹¹)—C(R¹²R¹³)—,wherein the left side of L₁ is attached to Ar and the right side of L₁is attached to the phenyl ring of Formula Ij. In some embodiments, L₁ is—C(X)—N(R¹¹)—, —C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or—N(R¹¹)—C(R¹²R¹³)—, and each R¹¹ and R⁴ are independently hydrogen orlower alkyl, wherein lower alkyl is optionally substituted with one ormore substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably each R¹¹ and R⁴ are H.

In some embodiments of compounds of Formula Ij, R² is hydrogen, fluoroor chloro, preferably fluoro or chloro. In some embodiments, R² ishydrogen, fluoro or chloro, each R¹ and R⁴ are independently hydrogen orlower alkyl, wherein lower alkyl is optionally substituted with one ormore substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably R² is fluoro or chloro and eachR¹¹ and R⁴ are H. In some embodiments, R² is hydrogen, fluoro or chloro,preferably fluoro or chloro, and L₁ is a bond, —N(R¹¹)—, —N(R¹¹)—C(X)—,—N(R¹¹)—S(O)₂₋, —N(R¹¹)—C(NH)—, —N(R¹¹)—C(X)—N(R¹¹)—, or—N(R¹¹)—S(O)₂—N(R¹¹)—, also —N(R¹¹)—, —N(R¹¹)—C(X)—, or —N(R¹¹)—S(O)₂—,also —N(R¹¹)—C(O)—, wherein the left side (i.e. —N(R¹¹)—) of L₁ isattached to Ar and the right side of L₁ is attached to the phenyl ringof Formula Ij. In some embodiments, R² is hydrogen, fluoro or chloro,preferably fluoro or chloro; L₁ is a bond, —N(R¹¹)—, —N(R¹¹)—C(X)—,—N(R¹¹)—S(O)₂—, —N(R¹¹)—C(NH)—, —N(R¹¹)—C(X)—N(R¹¹)—, or—N(R¹¹)—S(O)₂—N(R¹¹)—, also —N(R¹¹)—, —N(R¹¹)—C(X)—, or —N(R¹¹)—S(O)₂—,also —N(R¹¹)—C(O)—; and each R¹¹ and R⁴ are independently hydrogen orlower alkyl, wherein lower alkyl is optionally substituted with one ormore substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably each R¹¹ and R⁴ are H.

In some embodiments of compounds of Formula Ij, R² is hydrogen, fluoroor chloro, preferably fluoro or chloro. In some embodiments, R² ishydrogen, fluoro or chloro, each R¹¹ and R⁴ are independently hydrogenor lower alkyl, wherein lower alkyl is optionally substituted with oneor more substituents selected from the group consisting of fluoro, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluorosubstituted lower alkylthio, preferably R² is fluoro or chloro and eachR¹¹ and R⁴ are H. In some embodiments, R² is hydrogen, fluoro or chloro,preferably fluoro or chloro, and L₁ is —C(X)—N(R¹)—, —C(R¹²R¹³)—X—,—X—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or —N(R¹¹)—C(R¹²R¹³)—, wherein theleft side of L₁ is attached to Ar and the right side of L₁ is attachedto the phenyl ring of Formula Ij. In some embodiments, R² is hydrogen,fluoro or chloro, preferably fluoro or chloro; L₁ is —C(X)—N(R¹)—,—C(R¹²R¹³)—X—, —X—C(R¹²R¹³)—, —C(R¹²R¹³)—N(R¹¹)—, or —N(R¹¹)—C(R¹²R¹³)—;and each R¹¹ and R⁴ are independently hydrogen or lower alkyl, whereinlower alkyl is optionally substituted with one or more substituentsselected from the group consisting of fluoro, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, and fluoro substituted loweralkylthio, preferably each R¹¹ and R⁴ are H.

In some embodiments of compounds of Formula Ij, further to any of theabove embodiments of Formula Ij, R²² is mono-alkylamino, di-alkylamino,or optionally substituted heterocycloalkyl, preferably whereinheterocycloalkyl is a 5 or 6 membered nitrogen containingheterocycloalkyl, wherein a nitrogen of the heterocycloalkyl is bound tothe S(O)₂ of Formula Ij. In some embodiments, R²² is mono-alkylamino,di-alkylamino or 5 or 6 membered nitrogen containing heterocycloalkyl,wherein the heterocycloalkyl is substituted with one or moresubstituents selected from the group consisting of fluoro, —OH, —NH₂,lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino,di-alkylamino, and cycloalkylamino, wherein lower alkyl or the alkylchain(s) of lower alkoxy, lower alkylthio, mono-alkylamino, ordi-alkylamino are optionally substituted with one or more substituentsselected from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino,preferably wherein the 5 or 6 membered nitrogen containingheterocycloalkyl is optionally substituted with one or more substituentsselected from the group consisting of fluoro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, and fluoro substituted lower alkylthio.

In some embodiments of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, or Ij, further to any of the above embodiments of Formula I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij, Ar is monocyclic or bicyclicnitrogen containing heteroaryl. In some embodiments, Ar is selected fromthe group consisting of

wherein

indicates the attachment point of the Ar ring to L₁ in Formula I, Ia orIj, to L₃ in Formula If or Ig, to the nitrogen of Ar—N— in Formula Ib orId, to A of Formula Ih or Ii, or to the phenyl ring of Formula Ic or Ie,and wherein:

-   -   T, U, X, and Z at each occurrence are independently N or CH,        provided, however, that at least one, and no more than 2 of X in        any ring is N, no more than 2 of U in any ring is N, at least        one T is N and no more than two of T within any six-membered        ring is N, and at least one Z is N and no more than 2 of Z        within any bicyclic ring is N;    -   Y is NH, O, or S;    -   W at each occurrence is independently N or CH;    -   V is O, S, or NH, provided, however, that when V is O or S, at        least one of U in any ring or W in any ring is N; and    -   any R¹ is bound to Ar at any available NH or CH, preferably any        R¹ is independently R¹⁶, wherein R¹⁶ at each occurrence is        independently selected from the group consisting of —OH, —NH₂,        —CN, —NO₂, —C(O)—OH, —S(O)₂—NH₂, —C(O)—NH₂, —O—R¹⁷, —S—R¹⁷,        —N(R¹⁹)—R¹⁷, —N(R¹⁹)—C(O)—R¹⁷, —N(R¹⁹)—S(O)₂—R¹⁷, —S(O)₂—R¹⁷,        —C(O)—R¹⁷, —C(O)—O—R¹⁷, —C(O)—N(R¹⁹)—R¹⁷, —S(O)₂—N(R¹⁹)—R¹⁷,        halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl, wherein lower alkyl is optionally substituted with        one or more substituents selected from the group consisting of        fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R¹⁶, or as substituents of lower alkyl, are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)—OH,        —S(O)₂—NH₂, —C(O)—NH₂, —O—R¹⁸, —S—R¹⁸, —N(R¹⁹)—R¹⁸,        —N(R¹⁹)—C(O)—R¹⁸, —N(R¹⁹)—S(O)₂—R¹⁸, —S(O)₂—R¹⁸, —C(O)—R¹⁸,        —C(O)—O—R¹⁸, —C(O)—N(R¹⁹)—R¹⁸, —S(O)₂—N(R¹⁹)—R¹⁸, halogen, lower        alkyl, fluoro substituted lower alkyl, and cycloalkylamino;    -   R¹⁷ at each occurrence is independently selected from the group        consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl        and heteroaryl, wherein lower alkyl is optionally substituted        with one or more substituents selected from the group consisting        of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R¹⁷ or as substituents of lower alkyl are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)—OH,        —S(O)₂—NH₂, —C(O)—NH₂, —O—R¹⁸, —S—R¹⁸, —N(R¹⁹)—R¹⁸,        —N(R¹⁹)—C(O)—R¹⁸, —N(R¹⁹)—S(O)₂—R¹⁸, —S(O)₂—R¹⁸, —C(O)—R¹⁸,        —C(O)—O—R¹⁸, —C(O)—N(R¹⁹)—R¹⁸, —S(O)₂—N(R¹⁹)—R¹⁸, halogen, lower        alkyl, fluoro substituted lower alkyl, and cycloalkylamino;    -   R¹⁸ at each occurrence is independently selected from the group        consisting of lower alkyl, heterocycloalkyl and heteroaryl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino; and    -   R¹⁹ at each occurrence is independently hydrogen or lower alkyl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and        fluoro substituted lower alkylthio.

In some embodiments of compounds of Formula I, Ia, Ib, Id, If, Ig, Ih,Ii, or Ij, further to any of the above embodiments of Formula I, Ia, Ib,Id, If, Ig, Ih, Ii, or Ij, when L₁ is other than a bond, Ar is selectedfrom the group consisting of

wherein

indicates the attachment point of the Ar ring to L₁ in Formula I, Ia orIj, to L₃ in Formula If or Ig, to the nitrogen of Ar—N— in Formula Ib orId, or to A of Formula Ih or Ii, and wherein:

-   -   T₁, U₁, W₁, X₁, and Z₁ at each occurrence are independently N or        CH, provided, however, that at most 1 of T₁, U₁, X₁, and Z₁ is        N;    -   T₂ at each occurrence is independently N or CH, provided,        however, that at most 2 of T₂ are N;    -   Y and V₁ are O, S, or NH;    -   any R₁ is bound to Ar at any available NH or CH, preferably any        R₁ is independently R¹⁶, as defined in paragraph [0041],        preferably wherein R¹⁶ at each occurrence is independently        selected from the group consisting of halogen, —OH, —NH₂, —CN,        lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino,        di-alkylamino, and —NR²⁰R²¹, wherein lower alkyl and the alkyl        chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino or        di-alkylamino are optionally substituted with one or more,        preferably 1, 2, or 3 substituents selected from the group        consisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, or        cycloalkylamino; and    -   R²⁰ and R²¹ at each occurrence independently combine with the        nitrogen to which they are attached to form a 5-7 membered        heterocycloalkyl or 5-7 membered heterocycloalkyl substituted        with one or more substituents selected from the group consisting        of fluoro, —OH, —NH₂, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, and fluoro substituted lower alkylthio.

In some embodiments of compounds of Formula I, Ia, Ib, Id, If, Ig, Ih,Ii, or Ij, further to any of the above embodiments of Formula I, Ia, Ib,Id, If, Ig, Ih, Ii, or Ij, when L₁ is other than a bond, Ar is selectedfrom the group consisting of

wherein

indicates the attachment point of the Ar ring to L₁ in Formula I, Ia orIj, to L₃ in Formula If or Ig, to the nitrogen of Ar—N— in Formula Ib orId, or to A of Formula Ih or Ii, and wherein:

-   -   W₁ at each occurrence is independently N or CH;    -   Y and V₁ are 0, S, or NH;    -   p is 0, 1, 2 or 3; and    -   R¹⁶, substituting at any available CH or NH, is as defined in        paragraph [0041], preferably wherein R¹⁶ at each occurrence is        independently selected from the group consisting of halogen,        —OH, —NH₂, —CN, lower alkyl, lower alkoxy, lower alkylthio,        mono-alkylamino, di-alkylamino, and —NR²⁰R²¹, wherein lower        alkyl and the alkyl chain(s) of lower alkoxy, lower alkylthio,        mono-alkylamino or di-alkylamino are optionally substituted with        one or more, preferably 1, 2, or 3 substituents selected from        the group consisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, or        cycloalkylamino, wherein R²⁰ and R²¹ are as defined in paragraph        [0042].

In some embodiments of compounds of Formula I, Ia, Ib, Id, If, Ig, Ih,Ii, or Ij, further to any of the above embodiments of Formula I, Ia, Ib,Id, If, Ig, Ih, Ii, or Ij, when L₁ is other than a bond, Ar is selectedfrom the group consisting of

wherein

indicates the attachment point of the Ar ring to L₁ in Formula I, Ia orIj, to L₃ in Formula If or Ig, to the nitrogen of Ar—N— in Formula Ib orId, or to A of Formula Ih or Ii, and wherein:

-   -   p is 0, 1, 2 or 3; and    -   R¹⁶, substituting at any available CH or NH, is as defined in        paragraph [0041].

In some embodiments of compounds of Formula Ic or Ie, further to any ofthe above embodiments of Formula Ic or Ie, Ar is selected from the groupconsisting of

wherein

indicates the attachment point of the Ar ring to the phenyl ring ofFormula Ic or Ie, and wherein:

-   -   T₁, U₁, W₁ and Z₁ at each occurrence is independently N or CH,        provided, however, that at most 1 of T₁, U₁, and Z₁ is N;    -   T₂ is N or CH, provided, however, that no more than 2 of T₂ are        N;    -   V₁ is O, S, or NH; and    -   any R¹ is bound to Ar at any available NH or CH, preferably any        R¹ is independently R¹⁶, as defined in paragraph [0041],        preferably wherein R¹⁶ at each occurrence is independently        selected from the group consisting of halogen, —OH, —NH₂, —CN,        lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino,        di-alkylamino, and —NR²⁰R²¹, wherein lower alkyl and the alkyl        chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino or        di-alkylamino are optionally substituted with one or more,        preferably 1, 2, or 3 substituents selected from the group        consisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, or        cycloalkylamino, wherein R²⁰ and R²¹ are as defined in paragraph        [0042].

In some embodiments of compounds of Formula Ic or Ie, further to any ofthe above embodiments of Formula Ic or Ie, R¹ is selected from the groupconsisting of

wherein

indicates the attachment point of the Ar ring to the phenyl ring ofFormula Ic or Ie, and wherein:

-   -   W₁ is N or CH;    -   V₁ is O, S, or NH;    -   p is 0, 1, 2 or 3; and    -   R¹⁶, substituting at any available CH or NH, is as defined in        paragraph [0041], preferably wherein R¹⁶ at each occurrence is        independently selected from the group consisting of halogen,        —OH, —NH₂, —CN, lower alkyl, lower alkoxy, lower alkylthio,        mono-alkylamino, di-alkylamino, and —NR²⁰R²¹, wherein lower        alkyl and the alkyl chain(s) of lower alkoxy, lower alkylthio,        mono-alkylamino or di-alkylamino are optionally substituted with        one or more, preferably 1, 2, or 3 substituents selected from        the group consisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, or        cycloalkylamino, wherein R²⁰ and R²¹ are as defined in paragraph        [0042].

In some embodiments of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, or Ii, further to any of the above embodiments of Formula I, Ia,Ib, Ic, Id, Ie, If, Ig, Ih, or Ii, R³ is optionally substituted loweralkyl or optionally substituted C₃₋₆ cycloalkyl. In some embodiments, R³is lower alkyl or C₃₋₆ cycloalkyl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino,fluoro substituted di-alkylamino, cycloalkylamino, and C₃₋₅ cycloalkyl,and wherein C₃₋₆ cycloalkyl is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, —OH, —NH₂,lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, fluoro substitutedmono-alkylamino, di-alkylamino, and fluoro substituted di-alkylamino. Insome embodiments, R³ is lower alkyl or C₃₋₆ cycloalkyl, wherein loweralkyl or C₃₋₆ cycloalkyl are optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, and fluoro substitutedlower alkylthio. In some embodiments, R³ is optionally fluorosubstituted lower alkyl or optionally fluoro substituted C₃₋₆cycloalkyl. In some embodiments, R³ is lower alkyl, wherein lower alkylis optionally substituted with one or more substituents selected fromthe group consisting of fluoro, —OH, —NH₂, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, fluoro substituted loweralkylthio, mono-alkylamino, fluoro substituted mono-alkylamino,di-alkylamino, fluoro substituted di-alkylamino, cycloalkylamino, alsoone or more substituents selected from the group consisting of fluoro,—OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluorosubstituted mono-alkylamino, di-alkylamino, and fluoro substituteddi-alkylamino, also one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, and fluoro substituted lower alkylthio. In someembodiments, R³ is optionally fluoro substituted lower alkyl.

In some embodiments of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, or Ii, further to any of the above embodiments of Formula I, Ia,Ib, Ic, Id, Ie, If, Ig, Ih, or Ii, R³ is optionally substituted phenyl,also phenyl mono-substituted at the para position, also phenylmono-substituted at the meta position. In some embodiments, R³ is phenyloptionally substituted with one or more substituents selected from thegroup consisting of halogen, —CN, —NO₂, —OH, —NH₂, lower alkyl, loweralkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, andcycloalkylamino, wherein lower alkyl or the alkyl chain(s) of loweralkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino areoptionally substituted with one or more substituents selected from thegroup consisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substitutedlower alkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino, preferably whereinthe phenyl is mono-substituted at either the para or meta position. Insome embodiments, R³ is phenyl optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkyl,fluoro substituted lower alkyl, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, and fluoro substituted lower alkylthio,preferably wherein the phenyl is mono-substituted at either the para ormeta position.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamide    (P-0001),-   N-(6-Acetylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide    (P-0002),-   6-Chloro-2-fluoro-N-(6-methoxy-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamide    (P-0003),-   N-(2-Acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide    (P-0004),-   6-Chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamide    (P-0005),-   Pyrrolidine-1-carboxylic acid    {5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-yl}-amide    (P-0006),-   6-Chloro-N-(3,5-dimethyl-isoxazol-4-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide    (P-0007),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-benzamide    (P-0008),-   6-Chloro-N-(6-cyclopentylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide    (P-0009),-   6-Chloro-N-[5-(4-chloro-phenyl)-2H-pyrazol-3-yl]-2-fluoro-3-(propane-1-sulfonylamino)-benzamide    (P-0010),-   6-Chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(propane-1-sulfonylamino)-benzamide    (P-0011),-   6-Chloro-N-[5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2-fluoro-3-(propane-1-sulfonylamino)-benzamide    (P-0012),-   6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide    (P-0013),-   [2-[6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-4H-[1,3,4]thiadiazin-(5E)-ylidene]-acetic    acid ethyl ester (P-0014),-   6-Chloro-N-(6-cyclopropylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide    (P-0015),-   6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-3-yl}-benzamide    (P-0016),-   N-(6-Benzylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide    (P-0017),-   6-Chloro-2-fluoro-N-imidazo[1,2-a]pyridin-3-yl-3-(propane-1-sulfonylamino)-benzamide    (P-0018),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amide    (P-0019),-   N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzylamino]-pyridin-2-yl}-acetamide    (P-0020),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(quinolin-3-ylaminomethyl)-phenyl]-amide (P-0021),-   Propane-1-sulfonic acid    {3-[(6-chloro-pyridin-3-ylamino)-methyl]-2,4-difluoro-phenyl}-amide    (P-0022),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[(6-methoxy-pyridin-3-ylamino)-methyl]-phenyl}-amide    (P-0023),-   Quinoline-3-carboxylic acid    [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0024),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide    (P-0025),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide (P-0026),-   2,6-Difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide    (P-0027),-   6-Acetylamino-N-[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0028),-   6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0029),-   6-Acetylamino-N-[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0030),-   6-Acetylamino-N-[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0031),-   6-Acetylamino-N-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0032),-   6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0033),-   6-Acetylamino-N-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0034),-   6-Acetylamino-N-[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0035),-   6-Acetylamino-N-[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0036),-   6-Acetylamino-N-[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0037),-   6-Acetylamino-N-[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0038),-   6-Acetylamino-N-[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0039),-   6-Acetylamino-N-[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-nicotinamide    (P-0040),-   6-Acetylamino-N-[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-nicotinamide    (P-0041),-   6-Acetylamino-N-[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-nicotinamide    (P-0042),-   6-Acetylamino-N-[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-nicotinamide    (P-0043),-   6-Acetylamino-N-[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-nicotinamide    (P-0044),-   6-Acetylamino-N-[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-nicotinamide    (P-0045),-   6-Acetylamino-N-(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-nicotinamide    (P-0046),-   6-Acetylamino-N-[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-nicotinamide    (P-0047),-   6-Acetylamino-N-[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-nicotinamide    (P-0048),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide    (P-0049),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide    (P-0050),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0051),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0052),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0053),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide    (P-0054),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide    (P-0055),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0056),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0057),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide    (P-0058),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0059),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide    (P-0060),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-0061),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-0062),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide (P-0063),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide (P-0064),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide (P-0065),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide    (P-0066),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    (3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-0067),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide    (P-0068),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide    (P-0069),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide    (P-0070),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide    (P-0071),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0072),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0073),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0074),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide    (P-0075),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide    (P-0076),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0077),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0078),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide    (P-0079),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0080),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide    (P-0081),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-0082),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-0083),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide (P-0084),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide (P-0085),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide (P-0086),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide    (P-0087),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    (3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-0088),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide    (P-0089),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide    (P-0090),-   N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyloxy]-pyridin-2-yl}-acetamide    (P-0091),-   Propane-1-sulfonic acid    [3-(2-amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-amide    (P-0092),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-amide    (P-0093),-   N-{5-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzyloxy]-pyridin-2-yl}-acetamide    (P-0094),-   N-[3-(2-Amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide    (P-0095),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide    (P-0096),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-benzamide    (P-0097),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-benzamide    (P-0098),-   N-(6-Acetylamino-pyridin-3-yl)-3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0099),-   N-(6-Acetylamino-pyridin-3-yl)-3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0100),-   N-(6-Acetylamino-pyridin-3-yl)-3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0101),-   6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0102),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzamide    (P-0103),-   N-(6-Acetylamino-pyridin-3-yl)-3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0104),-   N-(6-Acetylamino-pyridin-3-yl)-3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0105),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-benzamide    (P-0106),-   N-(6-Acetylamino-pyridin-3-yl)-3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0107),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-benzamide    (P-0108),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-2-sulfonylamino)-benzamide    (P-0109),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-3-sulfonylamino)-benzamide    (P-0110),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(dimethylaminosulfonylamino)-benzamide    (P-0111),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(piperidine-1-sulfonylamino)-benzamide    (P-0112),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(morpholine-4-sulfonylamino)-benzamide    (P-0113),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-benzamide    (P-0114),-   N-(6-Acetylamino-pyridin-3-yl)-3-cyclopentanesulfonylamino-2,6-difluoro-benzamide    (P-0115),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-benzamide    (P-0116),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-benzamide    (P-0117),-   6-Acetylamino-N-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-nicotinamide    (P-0118),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0119),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0120),    and    any salt, prodrug, tautomer, or isomer thereof.

In reference to compounds herein, unless clearly indicated to thecontrary, specification of a compound or group of compounds includespharmaceutically acceptable salts of such compound(s), pharmaceuticallyacceptable formulations of such compound(s), prodrug(s), and allstereoisomers thereof. In reference to compositions, kits, methods ofuse, etc. of compounds of Formula I described herein, it is understood(unless indicated otherwise) that a compound of Formula I includes allsub-embodiments thereof (e.g. including Formula Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, and Ij and all embodiments as described above).

In one aspect, methods are provided for treating a protein kinasemediated disease or condition in an animal subject, wherein the methodinvolves administering to the subject an effective amount of one or morecompound(s) of Formula I. The terms “treat,” “therapy,” and like termsrefer to the administration of material, e.g., one or more compound(s)of Formula I, in an amount effective to prevent, alleviate, orameliorate one or more symptoms of a disease or condition, i.e.,indication, and/or to prolong the survival of the subject being treated.The term “protein kinase mediated disease or condition” refers to adisease or condition in which the biological function of a proteinkinase affects the development, and/or course, and/or symptoms of thedisease or condition, and/or in which modulation of the protein kinasealters the development, course, and/or symptoms of the disease orcondition. A protein kinase mediated disease or condition includes adisease or condition for which modulation provides a therapeuticbenefit, e.g. wherein treatment with protein kinase modulators,including compounds described herein, provides a therapeutic benefit tothe subject suffering from or at risk of the disease or condition. Inone aspect, the protein kinase modulator is an inhibitor of the proteinkinase. In one aspect, the method involves administering to the subjectan effective amount of one or more compound(s) of Formula I incombination with one or more other therapies for the disease orcondition.

In one aspect, methods are provided for treating a protein kinasemediated disease or condition in an animal subject, wherein the methodinvolves administering to the subject an effective amount of any one ormore compound(s) of Formula I.

In one aspect, the invention provides methods for treating a Raf proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of oneor more compound(s) of Formula I. The terms “Raf protein kinase mediateddisease or condition,” “Raf mediated disease or condition,” and the likerefer to a disease or condition in which the biological function of aRaf kinase, including any mutations thereof, affects the development,course, and/or symptoms of the disease or condition, and/or in whichmodulation of the Raf protein kinase alters the development, course,and/or symptoms of the disease or condition. The Raf protein kinaseincludes, but is not limited to, A-Raf, mutations of A-Raf, B-Raf,mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1. In someembodiments, the Raf protein kinase is B-Raf mutation V600E. In someembodiments, the Raf protein kinase is B-Raf mutation V600E/T529I. Insome embodiments, the disease or condition is a cancer that is amenableto treatment by an inhibitor of the V600E mutant B-Raf. In someembodiments, the disease or condition is a cancer that is amenable totreatment by an inhibitor of the V600E/T529I mutant B-Raf. The Rafprotein kinase mediated disease or condition includes a disease orcondition for which Raf modulation provides a therapeutic benefit, e.g.wherein treatment with Raf modulators, including compounds describedherein, provides a therapeutic benefit to the subject suffering from orat risk of the disease or condition. In one aspect, the Raf modulator isa Raf inhibitor. In one aspect, the method involves administering to thesubject an effective amount of a compound of Formula I in combinationwith one or more other therapies for the disease or condition.Similarly, the terms “A-Raf, B-Raf or c-Raf-1 protein kinase mediateddisease or condition,” “A-Raf, B-Raf or c-Raf-1 mediated disease orcondition,” and the like refer to a disease or condition in which thebiological function of an A-Raf, B-Raf or c-Raf-1 kinase, respectively,including any mutations thereof, affects the development, course, and/orsymptoms of the disease or condition, and/or in which modulation of theA-Raf, B-Raf or c-Raf-1 protein kinase, respectively, alters thedevelopment, course, and/or symptoms of the disease or condition.

In some embodiments, a compound of Formula I will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted kinase activity assay. In some embodiments, acompound of Formula I will have an IC₅₀ of less than 500 nm, less than100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5nM, or less than 1 nM with respect to at least one kinase selected fromthe group consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf,Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1,EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3,Flt4, Fms, Frk, Fyn, Gsk3a, Gsk33, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R,IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck,Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA,PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1,Pyk2, Ret, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB,Yes, and Zap70, including any mutations thereof.

In some embodiments, a compound of Formula I will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of Abl, Akt1, Akt2, Akt3,ALK, Alk5, A-Raf, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1,Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3a,Gsk33, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1,Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4,MAPKAPK2, Met, Mnk1, MLK1, p38, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKCbeta, PKC theta, Plk1, Pyk2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB,Yes, and Zap70, including any mutations thereof.

In some embodiments, a compound of Formula I will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of Abl, A-Raf, B-Raf, Btk,c-Raf-1, EGFR, EphB2, Erk2, Fak, FGFR1, Flt1, Flt3, Flt4, Fms, Irak4,Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP4K4, MAPKAPK2, Met,p38, PDGFRB, Pim1, PKC theta, Pyk2, Ret, Src, Stk6, TrkA, TrkB, Yes, andZap70, including any mutations thereof.

In some embodiments, a compound of Formula I will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of Abl, A-Raf, B-Raf, Btk,c-Raf-1, EGFR, EphB2, Erk2, Fak, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kit, Lck,Lyn, MAP2K1, MAP4K4, MAPKAPK2, Met, p38, Pim1, PKC theta, Pyk2, Src,Stk6, TrkA, TrkB, Yes, and Zap70, including any mutations thereof.

In some embodiments, a compound of Formula I will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of A-Raf, B-Raf, B-RafV600E mutant, B-Raf V600E/T529I mutant, c-Raf-1, Fak, FGFR1, FGFR2,FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2,Kdr, Src and Ret, including any mutations thereof.

In some embodiments, a compound of Formula I is an inhibitor of a Rafkinase and has an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Raf kinase activity assay. Insome embodiments, a compound of Formula I will have an IC₅₀ of less than500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10nM, less than 5 nM, or less than 1 nM with respect to A-Raf, B-Raf,c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant. In someembodiments, a compound of Formula I will selectively inhibit one Rafkinase relative to one or more other Raf kinases. In some embodiments,the compound of Formula I will selectively inhibit a mutation of the Rafkinase relative to the wild type kinase, for example B-Raf V600E mutantrelative to wild type B-Raf.

Further to any of the above mentioned embodiments, a compound of FormulaI will also inhibit the effects of a mutation of the kinase, including,but not limited to, a mutation that is related to a disease state, suchas a cancer. For example, B-Raf V600E mutant is present in a highpercentage of some cancers, such as melanoma, and compounds will inhibitthe kinase activity of this mutant.

Further to any of the above embodiments, a compound of Formula I mayselectively inhibit one kinase relative to one or more other kinases,where preferably inhibition is selective with respect to any of theother kinases, whether a kinase discussed herein, or other kinases. Insome embodiments, the compound may selectively inhibit the effects of amutation of the kinase relative to the wild type kinase, for exampleB-Raf V600E mutant relative to wild type B-Raf. Selective inhibition ofone kinase relative to another is such that the IC₅₀ for the one kinasemay be at least about 2-fold, also 5-fold, also 10-fold, also 20-fold,also 50-fold, or at least about 100-fold less than the IC₅₀ for any ofthe other kinases as determined in a generally accepted kinase activityassay.

In another aspect, compositions are provided that include atherapeutically effective amount of one or more compound(s) of Formula Iand at least one pharmaceutically acceptable carrier, excipient, and/ordiluent, including combinations of any two or more compounds of FormulaI. The composition can further include a plurality of differentpharmacologically active compounds, which can include a plurality ofcompounds of Formula I. In another aspect, the composition can includeone or more compounds of Formula I along with one or more compounds thatare therapeutically effective for the same disease indication. In oneaspect, the composition includes one or more compounds of Formula Ialong with one or more compounds that are therapeutically effective forthe same disease indication, wherein the compounds have a synergisticeffect on the disease indication. In one aspect, the compositionincludes one or more compounds of Formula I effective in treating acancer and one or more other compounds that are effective in treatingthe cancer, further wherein the compounds are synergistically effectivein treating the cancer.

In another aspect, methods are provided for modulating the activity of aprotein kinase selected from the group consisting of Abl, Akt1, Akt2,Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1,c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2,FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3a, Gsk33, HCK,Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3,Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2,Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKCalpha, PKC beta, PKC theta, Plk1, Pyk2, Ret, ROCK1, ROCK2, Ron, Src,Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, including anymutations thereof, by contacting the protein kinase with an effectiveamount of one or more compound(s) of Formula I.

In another aspect, methods are provided for treating a protein kinasemediated disease or condition in an animal subject, wherein the methodinvolves administering to the subject an effective amount of acomposition including one or more compound(s) of Formula I.

In one aspect, methods are provided for treating a disease or conditionmediated by a protein kinase selected from the group consisting of Abl,Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5,CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak,FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3a,Gsk33, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1,Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2,MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1,Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, ROCK1, ROCK2,Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, includingany mutations thereof, by administering to the subject an effectiveamount of a composition including one or more compound(s) of Formula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Btk, Cdk2,CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4,Erk2, Fak, Fms, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R,IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn,MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDPK1, Pim1,Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, Ron, Src, Stk6,Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, including any mutationsthereof, by administering to the subject an effective amount of acomposition including one or more compound(s) of Formula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2, Fak,FGFR1, Flt1, Flt3, Flt4, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck,Lyn, MAP2K1, MAP4K4, MAPKAPK2, Met, p38, PDGFRB, Pim1, PKC theta, Pyk2,Ret, Src, Stk6, TrkA, TrkB, Yes, and Zap70, including any mutationsthereof, by administering to the subject an effective amount of acomposition including one or more compound(s) of Formula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2, Fak,Fms, Irak4, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAP4K4, MAPKAPK2,Met, p38, Pim1, PKC theta, Pyk2, Src, Stk6, TrkA, TrkB, Yes, and Zap70,including any mutations thereof, by administering to the subject aneffective amount of a composition including one or more compound(s) ofFormula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T529Imutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Lck,Lyn, Met, Pim1, Pim2, Pim3, Pyk2, Kdr, Src and Ret, including anymutations thereof, by administering to the subject an effective amountof a composition including one or more compound(s) of Formula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, orB-Raf V600E/T529I mutant by administering to the subject an effectiveamount of a composition including one or more compound(s) of Formula I.In one aspect, the invention provides methods for treating a disease orcondition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, orB-Raf V600E/T529I mutant by administering to the subject an effectiveamount of a composition including one or more compound(s) of Formula Iin combination with one or more other suitable therapies for treatingthe disease. In one aspect, the invention provides methods for treatinga cancer mediated by B-Raf V600E mutant or B-Raf V600E/T529I mutant byadministering to the subject an effective amount of a compositionincluding one or more compound(s) of Formula I in combination with oneor more suitable anticancer therapies, such as one or morechemotherapeutic drugs.

In one aspect, the invention provides a method of treating a cancer byadministering to the subject an effective amount of a compositionincluding one or more compound(s) of Formula I, in combination with oneor more other therapies or medical procedures effective in treating thecancer. Other therapies or medical procedures include suitableanticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy,photodynamic therapy) or medical procedure (e.g. surgery, radiationtreatment, hyperthermia heating, bone marrow or stem cell transplant).In one aspect, the one or more suitable anticancer therapies or medicalprocedures is selected from treatment with a chemotherapeutic agent(e.g. chemotherapeutic drug), radiation treatment (e.g. x-ray, □-ray, orelectron, proton, neutron, or □ particle beam), hyperthermia heating(e.g. microwave, ultrasound, radiofrequency ablation), Vaccine therapy(e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vectorvaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine,dendritic cell peptide vaccines), gene therapy (e.g. Ad5CMV-p53 vector,adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha),photodynamic therapy (e.g. aminolevulinic acid, motexafin lutetium),surgery, and bone marrow and stem cell transplantation.

In a preferred embodiment, the invention provides a method of treating acancer by administering to the subject an effective amount of acomposition including one or more compound(s) of Formula I incombination with one or more suitable chemotherapeutic agents. In oneaspect, the one or more suitable chemotherapeutic agents is selectedfrom an alkylating agent, including, but not limited to, adozelesin,altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine,chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine,fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine,mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine,streptozocin, temozolomide, thiotepa, and treosulfan; an antibiotic,including, but not limited to, bleomycin, dactinomycin, daunorubicin,doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone,neocarzinostatin, pentostatin, and plicamycin; an antimetabolite,including, but not limited to, azacitidine, capecitabine, cladribine,clofarabine, cytarabine, decitabine, floxuridine, fludarabine,5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine,methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, andtrimetrexate; an immunotherapy, including, but not limited to,alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab,pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomabtiuxetan; a hormone or hormone antagonist, including, but not limitedto, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane,flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide,magestrol, raloxifene, tamoxifen, and toremifene; a taxane, including,but not limited to, DJ-927, docetaxel, TPI 287, paclitaxel andDHA-paclitaxel; a retinoid, including, but not limited to, alitretinoin,bexarotene, fenretinide, isotretinoin, and tretinoin; an alkaloid,including, but not limited to, etoposide, homoharringtonine, teniposide,vinblastine, vincristine, vindesine, and vinorelbine; an antiangiogenicagent, including, but not limited to, AE-941 (GW786034, Neovastat),ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; atopoisomerase inhibitor, including, but not limited to, amsacrine,edotecarin, exatecan, irinotecan (also active metabolite SN-38(7-ethyl-10-hydroxy-camptothecin)), rubitecan, topotecan, and9-aminocamptothecin; a kinase inhibitor, including, but not limited to,erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib,sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107,BMS-354825, BMS-599626, UCN-01 (7-hydroxy-staurosporine), and vatalanib;a targeted signal transduction inhibitor including, but not limited tobortezomib, geldanamycin, and rapamycin; a biological response modifier,including, but not limited to, imiquimod, interferon-0, andinterleukin-2; and other chemotherapeutics, including, but not limitedto 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),aminoglutethimide, asparaginase, bryostatin-1, cilengitide, E7389,ixabepilone, procarbazine, sulindac, temsirolimus, tipifarnib.Preferably, the method of treating a cancer involves administering tothe subject an effective amount of a composition including one or morecompound(s) of Formula I in combination with a chemotherapeutic agentselected from 5-fluorouracil, carboplatin, dacarbazine, gefitinib,oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab,cetuximab, or erlotinib.

In another aspect, the invention provides a method of treating orprophylaxis of a disease or condition in a mammal, by administering tothe mammal a therapeutically effective amount of one or more compound(s)of Formula I, a prodrug of such compound, a pharmaceutically acceptablesalt of such compound or prodrug, or a pharmaceutically acceptableformulation of such compound or prodrug. The compound can be alone orcan be part of a composition. In another aspect, the invention providesa method of treating or prophylaxis of a disease or condition in amammal, by administering to the mammal a therapeutically effectiveamount of one or more compound(s) of Formula I, a prodrug of suchcompound, a pharmaceutically acceptable salt of such compound orprodrug, or a pharmaceutically acceptable formulation of such compoundor prodrug in combination with one or more other suitable therapies forthe disease or condition.

In a related aspect, the invention provides kits that include acomposition as described herein. In some embodiments, the composition ispackaged, e.g., in a vial, bottle, flask, which may be further packaged,e.g., within a box, envelope, or bag; the composition is approved by theU.S. Food and Drug Administration or similar regulatory agency foradministration to a mammal, e.g., a human; the composition is approvedfor administration to a mammal, e.g., a human, for a protein kinasemediated disease or condition; the invention kit includes writteninstructions for use and/or other indication that the composition issuitable or approved for administration to a mammal, e.g., a human, fora protein kinase-mediated disease or condition; and the composition ispackaged in unit dose or single dose form, e.g., single dose pills,capsules, or the like.

In aspects involving treatment or prophylaxis of a disease or conditionwith the compounds of Formula I, the disease or condition is, forexample without limitation, neurologic diseases, including, but notlimited to, cerebrovascular ischemia, multi-infarct dementia, headinjury, spinal cord injury, Alzheimer's disease (AD), Parkinson'sdisease, amyotrophic lateral sclerosis, dementia, senile chorea, andHuntington's disease; neoplastic diseases and associated complications,including, but not limited to, chemotherapy-induced hypoxia,gastrointestinal stromal tumors (GISTs), prostate tumors, mast celltumors (including canine mast cell tumors), acute myeloid leukemia,acute lymphocytic leukemia, chronic myeloid leukemia, chroniclymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas,glioblastoma, astrocytoma, neuroblastoma, sarcomas (e.g. sarcomas ofneuroectodermal origin, leiomyosarcoma), carcinomas (e.g. lung, breast,pancreatic, colon, hepatocellular, renal, female genital tract, squamouscell, carcinoma in situ), lymphoma (e.g. histiocytic lymphoma,non-Hodgkin's lymphoma), MEN2 syndromes, neurofibromatosis (includingSchwann cell neoplasia), myelodysplastic syndrome, leukemia, tumorangiogenesis, cancers of the thyroid, liver, bone, skin, brain, centralnervous system, pancreas, lung (e.g. small cell lung cancer, non smallcell lung cancer), breast, colon, bladder, prostate, gastrointestinaltract, endometrium, fallopian tube, testes and ovary, and metastasis oftumors to other tissues; pain of neuropathic or inflammatory origin,including, but not limited to, acute pain, chronic pain, bone pain,cancer-related pain and migraine; cardiovascular diseases, including,but not limited to, heart failure, ischemic stroke, cardiac hypertrophy,thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis,reperfusion injury and ischemia (e.g. cerebrovascular ischemia, liverischemia); inflammation including, but not limited to, age-relatedmacular degeneration, rheumatoid arthritis, allergic rhinitis,inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease),systemic lupus erythematosis, Sjogren's Syndrome, Wegener'sgranulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave'sdisease, myasthenia gravis, multiple sclerosis, osteoarthritis,endometriosis, scarring (e.g. dermal, tissue), vascular restenosis,fibrotic disorders, hypereosinophilia, CNS inflammation, pancreatitis,nephritis, atopic dermatitis, and hepatitis; immunodeficiency diseases,including, but not limited to, severe combined immunodeficiency (SCID),organ transplant rejection, and graft versus host disease; renal orprostatic diseases, including, but not limited to, diabetic nephropathy,polycystic kidney disease, nephrosclerosis, glomerulonephritis,interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronicrenal failure, tubular necrosis, diabetes-associated renalcomplications, and hypertrophy; metabolic diseases, including, but notlimited to, type 1 diabetes, type 2 diabetes, metabolic syndrome,obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipolysisand obesity; infection, including, but not limited to, Helicobacterpylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonarydiseases, including, but not limited to, chronic obstructive pulmonarydisease (COPD), acute respiratory distress syndrome (ARDS), asthma,allergy, bronchitis, emphysema, and pulmonary fibrosis; geneticdevelopmental diseases, including, but not limited to, Noonan'ssyndrome, Crouzon syndrome, acrocephalo-syndactyly type I, Pfeiffer'ssyndrome, Jackson-Weiss syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneoussyndrome (CFC) and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;disorders of bone structure, mineralization and bone reformation andresorption, including, but not limited to, osteoporosis, increased riskof fracture, Paget's disease, hypercalcemia, and metastatis of cancer tobone; Grave's disease; Hirschsprung's disease; lymphoedema; selectiveT-cell defect (STD); X-linked agammaglobulinemia; diabetic retinopathy;alopecia; erectile dysfunction; tuberous sclerosis, and diseasesassociated with muscle regeneration or degeneration, including, but notlimited to, sarcopenia, muscular dystrophies (including, but not limitedto, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies),motor neuron diseases (including, but not limited to, amyotrophiclateral sclerosis, infantile progressive spinal muscular atrophy,intermediate spinal muscular atrophy, juvenile spinal muscular atrophy,spinal bulbar muscular atrophy, and adult spinal muscular atrophy),inflammatory myopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

In some aspects, compounds of Formula I can be used in the preparationof a medicament for the treatment of a disease or condition is, forexample without limitation, neurologic diseases, including, but notlimited to, cerebrovascular ischemia, multi-infarct dementia, headinjury, spinal cord injury, Alzheimer's disease (AD), Parkinson'sdisease, amyotrophic lateral sclerosis, dementia, senile chorea, andHuntington's disease; neoplastic diseases and associated complications,including, but not limited to, chemotherapy-induced hypoxia,gastrointestinal stromal tumors (GISTs), prostate tumors, mast celltumors (including canine mast cell tumors), acute myeloid leukemia,acute lymphocytic leukemia, chronic myeloid leukemia, chroniclymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas,glioblastoma, astrocytoma, neuroblastoma, sarcomas (e.g. sarcomas ofneuroectodermal origin, leiomyosarcoma), carcinomas (e.g. lung, breast,pancreatic, colon, hepatocellular, renal, female genital tract, squamouscell, carcinoma in situ), lymphoma (e.g. histiocytic lymphoma,non-Hodgkin's lymphoma), MEN2 syndromes, neurofibromatosis (includingSchwann cell neoplasia), myelodysplastic syndrome, leukemia, tumorangiogenesis, cancers of the thyroid, liver, bone, skin, brain, centralnervous system, pancreas, lung (e.g. small cell lung cancer, non smallcell lung cancer), breast, colon, bladder, prostate, gastrointestinaltract, endometrium, fallopian tube, testes and ovary, and metastasis oftumors to other tissues; pain of neuropathic or inflammatory origin,including, but not limited to, acute pain, chronic pain, bone pain,cancer-related pain and migraine; cardiovascular diseases, including,but not limited to, heart failure, ischemic stroke, cardiac hypertrophy,thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis,reperfusion injury and ischemia (e.g. cerebrovascular ischemia, liverischemia); inflammation including, but not limited to, age-relatedmacular degeneration, rheumatoid arthritis, allergic rhinitis,inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease),systemic lupus erythematosis, Sjogren's Syndrome, Wegener'sgranulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave'sdisease, myasthenia gravis, multiple sclerosis, osteoarthritis,endometriosis, scarring (e.g. dermal, tissue), vascular restenosis,fibrotic disorders, hypereosinophilia, CNS inflammation, pancreatitis,nephritis, atopic dermatitis, and hepatitis; immunodeficiency diseases,including, but not limited to, severe combined immunodeficiency (SCID),organ transplant rejection, and graft versus host disease; renal orprostatic diseases, including, but not limited to, diabetic nephropathy,polycystic kidney disease, nephrosclerosis, glomerulonephritis,interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronicrenal failure, tubular necrosis, diabetes-associated renalcomplications, and hypertrophy; metabolic diseases, including, but notlimited to, type 1 diabetes, type 2 diabetes, metabolic syndrome,obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipolysisand obesity; infection, including, but not limited to, Helicobacterpylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonarydiseases, including, but not limited to, chronic obstructive pulmonarydisease (COPD), acute respiratory distress syndrome (ARDS), asthma,allergy, bronchitis, emphysema, and pulmonary fibrosis; geneticdevelopmental diseases, including, but not limited to, Noonan'ssyndrome, Crouzon syndrome, acrocephalo-syndactyly type I, Pfeiffer'ssyndrome, Jackson-Weiss syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneoussyndrome (CFC) and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;disorders of bone structure, mineralization and bone reformation andresorption, including, but not limited to, osteoporosis, increased riskof fracture, Paget's disease, hypercalcemia, and metastatis of cancer tobone; Grave's disease; Hirschsprung's disease; lymphoedema; selectiveT-cell defect (STD); X-linked agammaglobulinemia; diabetic retinopathy;alopecia; erectile dysfunction; tuberous sclerosis, and diseasesassociated with muscle regeneration or degeneration, including, but notlimited to, sarcopenia, muscular dystrophies (including, but not limitedto, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies),motor neuron diseases (including, but not limited to, amyotrophiclateral sclerosis, infantile progressive spinal muscular atrophy,intermediate spinal muscular atrophy, juvenile spinal muscular atrophy,spinal bulbar muscular atrophy, and adult spinal muscular atrophy),inflammatory myopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

In aspects involving treatment or prophylaxis of a disease or conditionwith the compounds of Formula I, the invention provides methods fortreating an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediateddisease or condition in an animal subject (e.g. a mammal such as ahuman, other primates, sports animals, animals of commercial interestsuch as cattle, farm animals such as horses, or pets such as dogs andcats), e.g., a disease or condition characterized by abnormal A-Raf,B-Raf, and/or c-Raf-1 activity (e.g. kinase activity). Invention methodsinvolve administering to the subject suffering from or at risk of anA-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease orcondition an effective amount of compound of Formula I. In oneembodiment, the A-Raf-mediated, B-Raf-mediated, and/or c-Raf-1-mediateddisease is selected from the group consisting of neurologic diseases,including, but not limited to, multi-infarct dementia, head injury,spinal cord injury, Alzheimer's disease (AD), Parkinson's disease;neoplastic diseases including, but not limited to, melanoma, glioma,sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid,renal, ovarian), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis,acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumorangiogenesis, neuroendocrine tumors such as medullary thyroid cancer,carcinoid, small cell lung cancer and pheochromocytoma; pain ofneuropathic or inflammatory origin, including, but not limited to, acutepain, chronic pain, cancer-related pain, and migraine; cardiovasculardiseases including, but not limited to, heart failure, ischemic stroke,cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathysyndromes), atherosclerosis, and reperfusion injury; inflammationincluding, but not limited to, psoriasis, arthritis and autoimmunediseases and conditions, osteoarthritis, endometriosis, scarring,vascular restenosis, fibrotic disorders, rheumatoid arthritis,inflammatory bowel disease; immunodeficiency diseases, including, butnot limited to, organ transplant rejection, graft versus host disease;renal or prostatic diseases, including, but not limited to, diabeticnephropathy, polycystic kidney disease, nephrosclerosis,glomerulonephritis, prostate hyperplasia; metabolic disorders,including, but not limited to, obesity; infection, including, but notlimited to Helicobacter pylori, Hepatitis and Influenza viruses, fever,and sepsis; pulmonary diseases including, but not limited to, chronicobstructive pulmonary disease (COPD) and acute respiratory distresssyndrome (ARDS); genetic developmental diseases, including, but notlimited to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletalsyndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC), andneural crest syndrome abnormalities causing cardiovascular, skeletal,intestinal, skin, hair and endocrine diseases; and diseases associatedwith muscle regeneration or degeneration, including, but not limited to,sarcopenia, muscular dystrophies (including, but not limited to,Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies),motor neuron diseases (including, but not limited to, amyotrophiclateral sclerosis, infantile progressive spinal muscular atrophy,intermediate spinal muscular atrophy, juvenile spinal muscular atrophy,spinal bulbar muscular atrophy, and adult spinal muscular atrophy),inflammatory myopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

In some aspects, compounds of Formula I can be used in the preparationof a medicament for the treatment of an A-Raf-mediated, B-Raf-mediatedor c-Raf-1-mediated disease or condition selected from the groupconsisting of neurologic diseases, including, but not limited to,multi-infarct dementia, head injury, spinal cord injury, Alzheimer'sdisease (AD), Parkinson's disease; neoplastic diseases including, butnot limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal,lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia,myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrinetumors such as medullary thyroid cancer, carcinoid, small cell lungcancer and pheochromocytoma; pain of neuropathic or inflammatory origin,including, but not limited to, acute pain, chronic pain, cancer-relatedpain, and migraine; cardiovascular diseases, including, but not limitedto, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis(e.g. thrombotic microangiopathy syndromes), atherosclerosis, andreperfusion injury; inflammation including, but not limited to,psoriasis, arthritis and autoimmune diseases and conditions,osteoarthritis, endometriosis, scarring, vascular restenosis, fibroticdisorders, rheumatoid arthritis, inflammatory bowel disease;immunodeficiency diseases, including, but not limited to, organtransplant rejection, graft versus host disease; renal or prostaticdiseases, including, but not limited to, diabetic nephropathy,polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostatehyperplasia; metabolic disorders, including, but not limited to,obesity; infection, including, but not limited to, Helicobacter pylori,Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases,including, but not limited to, chronic obstructive pulmonary disease(COPD) and acute respiratory distress syndrome (ARDS); geneticdevelopmental diseases, including, but not limited to, Noonan'ssyndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARDsyndrome, cardio-faciocutaneous syndrome (CFC), and neural crestsyndrome abnormalities causing cardiovascular, skeletal, intestinal,skin, hair and endocrine diseases; and diseases associated with muscleregeneration or degeneration, including, but not limited to, sarcopenia,muscular dystrophies (including, but not limited to, Duchenne, Becker,Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic,Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motorneuron diseases (including, but not limited to, amyotrophic lateralsclerosis, infantile progressive spinal muscular atrophy, intermediatespinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbarmuscular atrophy, and adult spinal muscular atrophy), inflammatorymyopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

The compounds of Formula I with kinase activity IC₅₀ less than 10 □M asdetermined in a standard assay described herein can be used to treatprotein kinase mediated diseases and conditions related to the followingprotein kinases, including any mutations thereof, for example withoutlimitation:

-   -   Abl, related to chronic myeloid leukemia (CML), acute        lymphoblastic leukemia (ALL) and acute myelogenous leukemia        (AML);    -   Akt1, related to gastric, prostate, colorectal, ovarian,        pancreatic and breast cancer, glioblastoma and leukemia, as well        as schizophrenia and bipolar disorders, and also use in        combination with other chemotherapeutic drugs;    -   Akt2, related to hyperglycemia due to peripheral insulin        resistance and nonsuppressible hepatic glucose production        accompanied by inadequate compensatory hyperinsulinemia, also        related to pancreatic, ovarian and breast cancer;    -   Akt3, related to melanoma, prostate and breast cancer;    -   ALK, related to non-Hodgkin lymphomas such as diffuse large        B-cell lymphoma and anaplastic large cell lymphoma;    -   Alk5, related to pancreatic and biliary cancers, and cutaneous        T-cell lymphoma;    -   A-Raf, related to neurologic diseases such as multi-infarct        dementia, head injury, spinal cord injury, Alzheimer's disease        (AD), Parkinson's disease; neoplastic diseases including, but        not limited to, melanoma, glioma, sarcoma, carcinoma (e.g.        colorectal, lung, breast, pancreatic, thyroid, renal, ovarian),        lymphoma (e.g. histiocytic lymphoma), neurofibromatosis,        myelodysplastic syndrome, leukemia, tumor angiogenesis; pain of        neuropathic or inflammatory origin, including acute pain,        chronic pain, cancer-related pain and migraine; and diseases        associated with muscle regeneration or degeneration, including,        but not limited to, vascular restenosis, sarcopenia, muscular        dystrophies (including, but not limited to, Duchenne, Becker,        Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic,        Oculopharyngeal, Distal and Congenital Muscular Dystrophies),        motor neuron diseases (including, but not limited to,        amyotrophic lateral sclerosis, infantile progressive spinal        muscular atrophy, intermediate spinal muscular atrophy, juvenile        spinal muscular atrophy, spinal bulbar muscular atrophy, and        adult spinal muscular atrophy), inflammatory myopathies        (including, but not limited to, dermatomyositis, polymyositis,        and inclusion body myositis), diseases of the neuromuscular        junction (including, but not limited to, myasthenia gravis,        Lambert-Eaton syndrome, and congenital myasthenic syndrome),        myopathies due to endocrine abnormalities (including, but not        limited to, hyperthyroid myopathy and hypothyroid myopathy)        diseases of peripheral nerve (including, but not limited to,        Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and        Friedreich's ataxia), other myopathies (including, but not        limited to, myotonia congenita, paramyotonia congenita, central        core disease, nemaline myopathy, myotubular myopathy, and        periodic paralysis), and metabolic diseases of muscle        (including, but not limited to, phosphorylase deficiency, acid        maltase deficiency, phosphofructokinase deficiency, debrancher        enzyme deficiency, mitochondrial myopathy, carnitine deficiency,        carnitine palmatyl transferase deficiency, phosphoglycerate        kinase deficiency, phosphoglycerate mutase deficiency, lactate        dehydrogenase deficiency, and myoadenylate deaminase        deficiency);    -   B-Raf or c-Raf-1, related to neurologic diseases, including, but        not limited to, as multi-infarct dementia, head injury, spinal        cord injury, Alzheimer's disease (AD), Parkinson's disease;        neoplastic diseases including, but not limited to, melanoma,        glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast,        pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic        lymphoma) neurofibromatosis, acute myeloid leukemia,        myelodysplastic syndrome, leukemia, tumor angiogenesis,        neuroendocrine tumors such as medullary thyroid cancer,        carcinoid, small cell lung cancer and pheochromocytoma; pain of        neuropathic or inflammatory origin, including, but not limited        to, acute pain, chronic pain, cancer-related pain, and migraine;        cardiovascular diseases including, but not limited to, heart        failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.        thrombotic microangiopathy syndromes), atherosclerosis,        reperfusion injury; inflammation including, but not limited to,        psoriasis, arthritis and autoimmune diseases and conditions,        osteoarthritis, endometriosis, scarring, vascular restenosis,        fibrotic disorders, rheumatoid arthritis, inflammatory bowel        disease; immunodeficiency diseases, including, but not limited        to, organ transplant rejection, graft versus host disease; renal        or prostatic diseases, including, but not limited to, diabetic        nephropathy, polycystic kidney disease, nephrosclerosis,        glomerulonephritis, prostate hyperplasia; metabolic disorders,        including, but not limited to, obesity; infection, including,        but not limited to, Helicobacter pylori, Hepatitis and Influenza        viruses, fever, and sepsis; pulmonary diseases including, but        not limited to, chronic obstructive pulmonary disease (COPD) and        acute respiratory distress syndrome (ARDS); genetic        developmental diseases, including, but not limited to, Noonan's        syndrome, Costello syndrome, (faciocutaneoskeletal syndrome),        LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC), and        neural crest syndrome abnormalities causing cardiovascular,        skeletal, intestinal, skin, hair and endocrine diseases;    -   Brk, related to breast and colon cancer, and head and neck        squamous cell carcinoma;    -   Btk, related to X-linked agammaglobulinemia, acute lymphocytic        leukemia, autoimmune diseases such as multiple sclerosis,        systemic lupus erythematosis, rheumatoid arthritis, and Graves'        disease, immune suppression in organ transplant, and drug        sensitivity of B-lineage cells;    -   Cdk2, related to prostate, breast, colorectal and ovarian        cancer;    -   Cdk4, related to glioblastoma (e.g. glioblastoma multiforme),        anaplastic astrocytoma, and breast cancer;    -   Cdk5, related to Alzheimer's disease, amyotrophic lateral        sclerosis and Lewy body disease;    -   Cdk6, related to glioblastoma multiforme, non-Hodgkin's        lymphoma, splenic marginal zone lymphoma, T-cell lymphoblastic        lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia        (T-ALL);    -   CHK1, related to DNA damage repair, sensitizes cells to        chemotherapeutic agents;    -   Csk, related to colon and pancreatic carcinomas and autoimmune        pathology such as type 1 diabetes, rheumatoid arthritis and        systemic lupus erythematosus;    -   EGFR, related to breast, colorectal, bladder, prostate and non        small cell lung cancer, squamous cell carcinomas of the head and        neck cancer, oral cavity, and esophagus, and glioblastoma        multiforme;    -   EphA1, related to head and neck squamous cell carcinoma,        hepatoma and lung cancer;    -   EphA2, related to aberrant short-range contact-mediated axonal        guidance, bladder, breast, prostate, colon, skin, cervical,        ovarian, pancreatic and lung cancers, and metastatic melanoma;    -   EphB2, related to angiogenesis disorder (e.g. ocular        angiogenesis disease such as retinopathy), and cancer (e.g.        glioblastoma, breast and liver cancer);    -   EphB4, related to colorectal cancer (CRC), head and neck        squamous cell carcinoma, and tumours of the prostate, breast,        endometrium, and bladder;    -   Erk2, related to aberrant proliferation, differentiation,        transcription regulation and development, and may be useful in        treating inflammation, for example inflammation associated with        Lyme neuroborreliosis, and in treating cancers, such as gastric        cancer;    -   Fak, related to colon and breast tumors, and is also related to        esophageal squamous cell carcinoma, melanoma, anaplastic        astrocytoma, glioblastoma, ductal carcinoma in situ, prostate        and hepatocellular carcinoma, and tumor metastases, and may also        provide synergistic effects when used with other        chemotherapeutic drugs;    -   FGFR1, related to 8p11 myeloproliferative syndrome;    -   FGFR2, related to Crouzon Syndrome, Jackson-Weiss Syndrome,        Apert Syndrome, craniosynostosis, Pfeiffer Syndrome, acrocephalo        syndactyly type V, and Beare-Stevenson Cutis Gyrata Syndrome;    -   FGFR3, related to angiogenesis, wound healing, achondroplasia,        Muenke craniosynostosis, Crouzon syndrome, acanthosis nigricans,        thanatophoric dysplasia, bladder carcinomas, and multiple        myeloma;    -   FGFR4, related to cancer of the breast, lung, colon, medullary        thyroid, pancreas, ovary, prostate, endometrium, and fallopian        tube, head and neck squamous cell carcinomas and leiomyosarcoma;    -   Flt1, related to non-small cell lung carcinoma, prostate        carcinoma, and colorectal cancer;    -   Flt3, related to acute myeloid leukemia, myelodysplastic        syndrome, acute lymphoblastic leukemia;    -   Flt4, related to primary lymphoedema;    -   Fms, related to immune disorders, including rheumatoid        arthritis, systemic lupus erythematosis (SLE), and transplant        rejection, inflammatory diseases including inflammatory bowel        disease (e.g. ulcerative colitis, Crohn's disease), chronic        obstructive pulmonary disease (COPD), emphysema, and        atherosclerosis, metabolic disorders, including Type I diabetes,        Type II diabetes, insulin resistance, hyperglycemia, and        lipolysis, disorders of bone structure, mineralization and bone        formation and resorption, including osteoporosis, increased risk        of fracture, Paget's disease, hypercalcemia, and metastasis of        cancer to bone, kidney diseases, including nephritis (e.g.        glomerulonephritis, interstitial nephritis, Lupus nephritis),        tubular necrosis, diabetes-associated renal complications (e.g.        diabetic nephropathy), and hypertrophy, disorders of the central        nervous system, including multiple sclerosis, stroke,        Alzheimer's disease and Parkinson's disease; inflammatory and        chronic pain, including bone pain; and cancers, including        multiple myeloma, acute myeloid leukemia, chronic myeloid        leukemia (CML), prostate cancer, breast cancer, ovarian cancer,        and metastasis of tumors to other tissues;    -   Frk, related to acute myeloid leukemia and type 1 diabetes;    -   Fyn, related to Alzheimer's disease, schizophrenia and        prevention of metastases, e.g. in melanoma and squamous cell        carcinoma;    -   GSK3 (Gsk3α and/or Gsk3β), related to CNS disorders such as        Alzheimer's disease, Parkinson's disease, amyotrophic lateral        sclerosis, diabetes type II, bipolar disorders, stroke, cancer,        chronic inflammatory disease, leucopenia, schizophrenia, chronic        pain, neuropathic pain, and traumatic head injury;    -   HCK, related to chronic myelogenous leukemia and acute        lymphocytic leukemia;    -   Her2/Erbb2, related to prostate and breast cancer;    -   Her4/Erbb4, related to childhood medulloblastoma;    -   IGF1R, related to prostate cancer, hepatocellular carcinoma;    -   IKK beta, related to leukemia of T-cells, necrosis, insulin        resistance, and malignant neoplasms;    -   Irak4, related to bacterial infections, immunodeficiency        syndrome, inflammatory bowel disease (e.g. ulcerative colitis,        Crohn's disease), asthma, chronic bronchitis, cardio        hypertrophy, and kidney hypertension;    -   Itk, related to allergic asthma;    -   Jak1, related to Hepatitis C virus infection;    -   Jak2, related to myeloproliferative disorders such as        polycythaemia vera, myelofibrosis, essential thrombocythemia,        myeloid metaplasia and leukemias, including acute lymphoblastic        leukemia, chronic neutrophilic leukemia, juvenile myelomonocytic        leukemia, CMML, Philadelphia chromosome-negative CML,        megakaryocytic leukemia, and acute erythroid leukemia;    -   Jak3, related to X-linked severe combined immunodeficiency,        myeloproliferative disorders, transplant rejection and        autoimmune diseases such as rheumatoid arthritis, inflammatory        bowel disease (e.g. ulcerative colitis, Crohn's disease),        systemic lupus erythematosis, psoriasis and multiple sclerosis;    -   Jnk (Jnk1, Jnk2, Jnk3), related to metabolic diseases including        type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity,        and hepatic steatosis; cardiovascular diseases such as        atherosclerosis, ischemia (e.g. cerebrovascular ischemia, liver        ischemia), reperfusion injury, cardiac hypertrophy; renal        diseases such as chronic renal failure; neoplastic diseases and        associated complications, including chemotherapy-induced        hypoxia, prostate tumors, myeloid leukemia and cancers of the        liver, bone, skin, brain, pancreas, lung breast, colon, prostate        and ovary; transplant rejection; pain of neuropathic or        inflammatory origin including acute and chronic pain;        inflammatory and autoimmune diseases including age-related        macular degeneration, rheumatoid arthritis, inflammatory bowel        disease (e.g. ulcerative colitis, Crohn's disease), systemic        lupus erythematosis, Sjogren's Syndrome, psoriasis, scleroderma,        chronic thyroiditis, Grave's disease, myasthenia gravis, and        multiple sclerosis, and inflammation in other organs including        CNS inflammation, pancreatitis, nephritis, atopic dermatitis,        and hepatitis; airway inflammatory diseases such as asthma,        allergy, bronchitis, pulmonary fibrosis, chronic obstructive        pulmonary disease; neurologic diseases such as stroke,        cerebrovascular ischemia, neurodegenerative diseases such as        Parkinson's disease, Alzheimer's disease, amyotrophic lateral        sclerosis, dementia, senile chorea, head and spinal cord trauma,        and Huntington's disease. More particularly, Jnk1 is related to        type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity        and hepatic steatosis, Jnk2 is related to atherosclerosis, and        Jnk3 is related to inflammatory diseases including autoimmune        diseases such as rheumatoid arthritis, inflammatory bowel        disease (e.g. ulcerative colitis, Crohn's disease), systemic        lupus erythematosis, Sjogren's Syndrome, psoriasis and multiple        sclerosis, airway inflammatory diseases such as asthma, allergy,        pulmonary fibrosis, and chronic obstructive pulmonary disease,        and inflammation in other organs, such as CNS inflammation,        pancreatitis, nephritis, and hepatitis; neurologic diseases such        as stroke, cerebrovascular ischemia, and neurodegenerative        diseases such as Parkinson's disease, Alzheimer's disease, and        Huntington's disease; and neoplastic diseases such as prostate        tumors and myeloid leukemia;    -   Kdr, related to anti-angiogenesis for treating solid tumor        growth (e.g. ovarian, lung, breast, pancreatic, prostate, colon,        gastrointestinal stromal tumor, non small cell lung cancer, and        epidermoid cancer), metastasis, psoriasis, rheumatoid arthritis,        diabetic retinopathy and age related macular degeneration;    -   Kit, related to malignancies, including mast cell tumors, small        cell lung cancer, testicular cancer, gastrointestinal stromal        tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma,        carcinomas of the female genital tract, sarcomas of        neuroectodermal origin, colorectal carcinoma, carcinoma in situ,        Schwann cell neoplasia associated with neurofibromatosis, acute        myelocytic leukemia, acute lymphocytic leukemia, chronic        myelogenous leukemia, mastocytosis, melanoma, and canine mast        cell tumors, and inflammatory diseases, including asthma,        rheumatoid arthritis, allergic rhinitis, multiple sclerosis,        inflammatory bowel disease (e.g. ulcerative colitis, Crohn's        disease), transplant rejection, and hypereosinophilia;    -   Lck, related to acute lymphoblastic leukemia, T-cell lymphoma,        lymphopenia, renal carcinoma, colon carcinoma, severe combined        immunodeficiency, multiple sclerosis, inflammatory bowel disease        (e.g. ulcerative colitis, Crohn's disease) and type I diabetes;    -   Lyn, related to cancers such as glioblastoma.    -   MAP2K1, related to acute myeloid leukemia, breast, ovarian and        liver cancer;    -   MAP2K2, related to cancer and inflammation;    -   MAP4K4, related to metabolic indications, including        re-sensitizing fat and muscle cells to insulin, ameliorating the        pathology in adipocytes, ameliorating the pathology in muscle        cells, metabolic syndrome, and type II diabetes; a broad range        of oncology indications, including blocking the migration,        invasion and metastasis in many different tumor types; and        T-cell mediated autoimmune diseases;    -   MAPKAPK2, cancer (e.g. prostate, breast), stroke, menengitis,        and inflammatory disorders;    -   Met, related to kidney, breast, bladder, non-small-cell lung,        colorectal, and bladder cancers, and hepatocellular carcinoma;    -   Mnk1, related to conditions associated with heat shock, nutrient        deprivation, oxidative or osmotic stress, and infection of        mammalian cells (e.g. with viruses such as adenovirus (Ad) or        influenza virus), and autoimmune diseases;    -   MLK1, related to neurodegenerative diseases such as Alzheimer's        disease and Parkinson's disease, and inflammatory disorders;    -   p38, related to acute coronary syndrome, stroke,        atherosclerosis, and inflammatory autoimmune diseases such as        rheumatoid arthritis, and inflammatory bowel disease (e.g.        ulcerative colitis, Crohn's disease); PDGFR (PDGFRA, PDGFRB),        related to idiopathic hypereosinophilic syndrome, chronic        eosinophilic leukemia, glioma, gastrointestinal stromal tumors        (GISTs), juvenile myelomonocytic leukemia, metastatic        medulloblastoma, atherogenesis, and restenosis. More        particularly, PDGFRA related to idiopathic hypereosinophilic        syndrome, chronic eosinophilic leukemia, glioma,        gastrointestinal stromal tumors (GISTs), juvenile myelomonocytic        leukemia, metastatic medulloblastoma, atherogenesis, and        restenosis, and PDGFRB related to idiopathic hypereosinophilic        syndrome, chronic eosinophilic leukemia, juvenile myelomonocytic        leukemia, and metastatic medulloblastoma;    -   PDPK1, related to cancer and diabetes;    -   Pim1, related to cancers such as hematopoietic (e.g. acute        myeloid and acute lymphoid leukemias) and prostate cancers, and        non-Hodgkin's lymphomas;    -   Pim2, related to lymphomas;    -   Pim3, related to hepatocellular carcinoma;    -   PKC alpha, related to pituitary tumors and prefrontal cortical        dysfunction such as distractibility, impaired judgment,        impulsivity, and thought disorder, also may be used to sensitize        chemotherapy in breast, colon, and non small cell lung cancers;    -   PKC beta, related to diabetic retinopathy;    -   PKC-theta, related to insulin resistance, T-cell lymphoma;    -   Plk1, related to cancers (e.g. lymphoma of the thyroid,        non-Hodgkin's lymphomas, colorectal cancers, leukemias and        melanoma), also useful as sensitizer in chemotherapy;    -   Pyk2, related to inflammation (e.g. osteoporosis, polycystic        kidney disease, rheumatoid arthritis and inflammatory bowel        disease), CNS disease (e.g. Parkinson's disease and Alzheimer's        disease), stroke and cancers (e.g. gliomas, breast cancer, and        pancreatic cancer);    -   Ret, related to cancer of the thyroid, neuroblastoma, familial        medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia        type IIA and IIB (MEN2A, MEN2B), and neurodegenerative disorders        (e.g. Hirschsprung's disease, Parkinson's disease, Alzheimer's        disease, and amyotrophic lateral sclerosis);    -   ROCK (ROCK-1, ROCK-2), related to cancers (e.g. ovarian cancer,        hepatocellular carcinoma, pancreatic cancer), ocular disease        (e.g. glaucoma), cardiac hypertrophy, improved renal perfusion,        transplant rejection, and acute respiratory distress syndrome;    -   Ron, related to cancer and inflammation;    -   Src, related to cancer and osteoporosis;    -   Stk6, related to gastric, bladder, breast, lung, CNS, ovarian,        kidney, colon, prostate, pancreas, and cervical cancers,        melanoma, leukemia, and neuroblastoma;    -   Syk, related to lymphomas (e.g. mantle cell lymphoma);    -   TEC, related to sepsis, septic shock, inflammation, rheumatoid        arthritis, Crohn's disease, irritable bowel disease (IBD) and        ulcerative colitis;    -   Tie2 (TEK), related to cancer, arthritis (e.g. rheumatoid        arthritis), and atherosclerosis;    -   TrkA, related to pain (e.g. chronic pain, neuropathic pain),        cancer (e.g. prostate cancer, lung cancer, pancreatic cancer),        allergic disorders (e.g. asthma), arthritis, diabetic        retinopathy, macular degeneration and psoriasis;    -   TrkB, related to obesity, hyperphagia, developmental delays,        cancer (e.g. prostate cancer, lung cancer, Wilms tumors,        neuroblastoma, pancreatic cancer), various neuropathies (e.g.        stroke, multiple sclerosis, transverse myelitis, and        encephalitis), and diabetes.    -   Yes, related to various cancers including esophageal squamous        cell carcinoma; and    -   Zap70, related to AIDS, systemic lupus erythematosus, myasthenia        gravis, atherosclerosis, rejection of transplanted organs or        tissues, allograft rejection including acute and chronic        allograft rejection, graft versus host disease, rheumatoid        arthritis, psoriasis, systemic sclerosis, atopic dermatitis,        eczematous dermatitis, alopecia, and inflammation of the nasal        mucus membrane, including all forms of rhinitis.

Additional aspects and embodiments will be apparent from the followingDetailed Description of the Invention and from the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the following definitions apply unless clearly indicatedotherwise:

“Halogen” refer to all halogens, that is, chloro (Cl), fluoro (F), bromo(Br), or iodo (I).

“Hydroxyl” or “hydroxy” refer to the group —OH.

“Thiol” refers to the group —SH.

“Lower alkyl” alone or in combination means an alkane-derived radicalcontaining from 1 to 6 carbon atoms (unless specifically defined) thatincludes a straight chain alkyl or branched alkyl. The straight chain orbranched alkyl group is chemically feasible and attached at anyavailable point to produce a stable compound. In many embodiments, alower alkyl is a straight or branched alkyl group containing from 1-6,1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl,butyl, t-butyl, and the like. An “optionally substituted lower alkyl”denotes lower alkyl that is optionally independently substituted, unlessindicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also1, 2, or 3 substituents, attached at any available atom to produce astable compound, wherein the substituents are selected from the groupconsisting of —F, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂,—C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂,—C(NH)—NH₂, —O—R^(o), —S—R^(o), —O—C(O)—R^(o), —O—C(S)—R^(o),—C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o), —C(S)—O—R^(o), —S(O)—R^(o),—S(O)₂—R^(o), —C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o),—C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o),—C(NH)—N(H)—R^(o), —C(NH)—N(R^(P))—R^(o), —N(H)—C(O)—R^(o),—N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o),—N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o),—N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂,—N(R^(o))—C(O)—N(H)—R^(o), —N(R^(o))—C(S)—N(H)—R^(o),—N(H)—C(O)—N(R^(o))—R^(o), —N(H)—C(S)—N(R^(o))—R^(o),—N(R^(o))—C(O)—N(R^(o))—R^(o), —N(R^(o))—C(S)—N(R^(o))—R^(o),—N(H)—S(O)₂—N(H)—R^(o), —N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(e), —R^(f), and —R^(g). Furthermore, possiblesubstitutions include subsets of these substitutions, such as areindicated herein, for example, in the description of compounds ofFormula I, attached at any available atom to produce a stable compound.For example “fluoro substituted lower alkyl” denotes a lower alkyl groupsubstituted with one or more fluoro atoms, such as perfluoroalkyl, wherepreferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoroatoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutionsare chemically feasible and attached at any available atom to provide astable compound.

“Lower alkenyl” alone or in combination means a straight or branchedhydrocarbon containing 2-6 carbon atoms (unless specifically defined)and at least one, preferably 1-3, more preferably 1-2, most preferablyone, carbon to carbon double bond. Carbon to carbon double bonds may beeither contained within a straight chain or branched portion. Thestraight chain or branched lower alkenyl group is chemically feasibleand attached at any available point to provide a stable compound.Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl,butenyl, and the like. An “optionally substituted lower alkenyl” denoteslower alkenyl that is optionally independently substituted, unlessindicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also1, 2, or 3 substituents, attached at any available atom to produce astable compound, wherein the substituents are selected from the groupconsisting of —F, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂,—C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂,—C(NH)—NH₂, —O—R^(o), —S—R^(o), —O—C(O)—R^(o), —O—C(S)—R^(o),—C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o), —C(S)—O—R^(o), —S(O)—R^(o),—S(O)₂—R^(o), —C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o),—C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o),—C(NH)—N(H)—R^(o), —C(NH)—N(R^(P))—R^(o), —N(H)—C(O)—R^(o),—N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o),—N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o),—N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂,—N(R^(o))—C(O)—N(H)—R^(o), —N(R^(o))—C(S)—N(H)—R^(o),—N(H)—C(O)—N(R^(o))—R^(o), —N(H)—C(S)—N(R^(o))—R^(o),—N(R^(o))—C(O)—N(R^(o))—R^(o), —N(R^(o))—C(S)—N(R^(o))—R^(o),—N(H)—S(O)₂—N(H)—R^(o), —N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(f), and —R^(g). Further, possiblesubstitutions include subsets of these substitutions, such as areindicated herein, for example, in the description of compounds ofFormula I, attached at any available atom to produce a stable compound.For example “fluoro substituted lower alkenyl” denotes a lower alkenylgroup substituted with one or more fluoro atoms, where preferably thelower alkenyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1,2, or 3 fluoro atoms. “C₃₋₆ alkenyl” denotes lower alkenyl containing3-6 carbon atoms. An “optionally substituted C₃₋₆ alkenyl” denotesoptionally substituted lower alkenyl containing 3-6 carbon atoms. It isunderstood that substitutions are chemically feasible and attached atany available atom to provide a stable compound.

“Lower alkynyl” alone or in combination means a straight or branchedhydrocarbon containing 2-6 carbon atoms (unless specifically defined)containing at least one, preferably one, carbon to carbon triple bond.The straight chain or branched lower alkynyl group is chemicallyfeasible and attached at any available point to provide a stablecompound. Examples of alkynyl groups include ethynyl, propynyl, butynyl,and the like. An “optionally substituted lower alkynyl” denotes loweralkynyl that is optionally independently substituted, unless indicatedotherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3substituents, attached at any available atom to produce a stablecompound, wherein the substituents are selected from the groupconsisting of —F, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂,—C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂,—C(NH)—NH₂, —O—R^(o), —S—R^(o), —O—C(O)—R^(o), —O—C(S)—R^(o),—C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o), —C(S)—O—R^(o), —S(O)—R^(o),—S(O)₂—R^(o), —C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o),—C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o),—C(NH)—N(H)—R^(o), —C(NH)—N(R^(P))—R^(o), —N(H)—C(O)—R^(o),—N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o),—N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o),—N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂,—N(R^(o))—C(O)—N(H)—R^(o), —N(R^(o))—C(S)—N(H)—R^(o),—N(H)—C(O)—N(R^(o))—R^(o), —N(H)—C(S)—N(R^(o))—R^(o),—N(R^(o))—C(O)—N(R^(o))—R^(o), —N(R^(o))—C(S)—N(R^(o))—R^(o),—N(H)—S(O)₂—N(H)—R^(o), —N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), and —R^(g). Further, possiblesubstitutions include subsets of these substitutions, such as areindicated herein, for example, in the description of compounds ofFormula I, attached at any available atom to produce a stable compound.For example “fluoro substituted lower alkynyl” denotes a lower alkynylgroup substituted with one or more fluoro atoms, where preferably thelower alkynyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1,2, or 3 fluoro atoms. “C₃₋₆ alkynyl” denotes lower alkynyl containing3-6 carbon atoms. An “optionally substituted C₃₋₆ alkynyl” denotesoptionally substituted lower alkynyl containing 3-6 carbon atoms. It isunderstood that substitutions are chemically feasible and attached atany available atom to provide a stable compound.

“Cycloalkyl” refers to saturated or unsaturated, non-aromaticmonocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8,more preferably 3-6, ring members per ring, such as cyclopropyl,cyclopentyl, cyclohexyl, adamantyl, and the like. An “optionallysubstituted cycloalkyl” is a cycloalkyl that is optionally independentlysubstituted, unless indicated otherwise, with one or more, preferably 1,2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any availableatom to produce a stable compound, wherein the substituents are selectedfrom the group consisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)—OH,—C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂,—N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o), —S—R^(o),—O—C(O)—R^(o), —O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o),—C(S)—O—R^(o), —S(O)—R^(o), —S(O)₂—R^(o), —C(O)—N(H)—R^(o),—C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o), —C(S)—N(R^(o))—R^(o),—S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o), —C(NH)—N(H)—R^(o),—C(NH)—N(R^(P))—R^(o), —N(H)—C(O)—R^(o), —N(H)—C(S)—R^(o),—N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o), —N(H)—S(O)₂—R^(o),—N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o), —N(H)—C(S)—N(H)—R^(o),—N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂, —N(R^(o))—C(O)—N(H)—R^(o),—N(R^(o))—C(S)—N(H)—R^(o), —N(H)—C(O)—N(R^(o))—R^(o),—N(H)—C(S)—N(R^(o))—R^(o), —N(R^(o))—C(O)—N(R^(o))—R^(o),—N(R^(o))—C(S)—N(R^(o))—R^(o), —N(H)—S(O)₂—N(H)—R^(o),—N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), —R^(f), and —R^(g). “C₃₋₆ cycloalkyl”denotes cycloalkyl containing 3-6 carbon atoms. “C₃₋₅ cycloalkyl”denotes cycloalkyl containing 3-5 carbon atoms. It is understood thatsubstitutions are chemically feasible and attached at any available atomto provide a stable compound.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticcycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbonatoms in the ring are replaced by heteroatoms of O, S or N, and areoptionally fused with benzo or heteroaryl of 5-6 ring members.Heterocycloalkyl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.Heterocycloalkyl is also intended to include compounds in which a ringcarbon may be oxo substituted, i.e. the ring carbon is a carbonyl group,such as lactones and lactams. The point of attachment of theheterocycloalkyl ring is at a carbon or nitrogen atom such that a stablering is retained. Examples of heterocycloalkyl groups include, but arenot limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl,piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl,and dihydroindolyl. “Nitrogen containing heterocycloalkyl” refers toheterocycloalkyl wherein at least one heteroatom is N. An “optionallysubstituted heterocycloalkyl” is a heterocycloalkyl that is optionallyindependently substituted, unless indicated otherwise, with one or more,preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached atany available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of halogen, —OH,—NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂,—N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o),—S—R^(o), —O—C(O)—R^(o), —O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o),—C(O)—O—R^(o), —C(S)—O—R^(o), —S(O)—R^(o), —S(O)₂—R^(o),—C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o),—C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o),—C(NH)—N(H)—R^(o), —C(NH)—N(R^(P))—R^(o), —N(H)—C(O)—R^(o),—N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o),—N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o),—N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂,—N(R^(o))—C(O)—N(H)—R^(o), —N(R^(o))—C(S)—N(H)—R^(o),—N(H)—C(O)—N(R^(o))—R^(o), —N(H)—C(S)—N(R^(o))—R^(o),—N(R^(o))—C(O)—N(R^(o))—R^(o), —N(R^(o))—C(S)—N(R^(o))—R^(o),—N(H)—S(O)₂—N(H)—R^(o), —N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), —R^(f), and —R^(g). It is understoodthat substitutions are chemically feasible and attached at any availableatom to provide a stable compound.

“Aryl” alone or in combination refers to a monocyclic or bicyclic ringsystem containing aromatic hydrocarbons such as phenyl or naphthyl,which may be optionally fused with a cycloalkyl of preferably 5-7, morepreferably 5-6, ring members. An “optionally substituted aryl” is anaryl that is optionally independently substituted, unless indicatedotherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3substituents, attached at any available atom to produce a stablecompound, wherein the substituents are selected from the groupconsisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH,—C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂,—N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o), —S—R^(o), —O—C(O)—R^(o),—O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o), —C(S)—O—R^(o),—S(O)—R^(o), —S(O)₂—R^(o), —C(O)—N(H)—R^(o), —C(S)—N(H)—R^(o),—C(O)—N(R^(o))—R^(o), —C(S)—N(R^(o))—R^(o), —S(O)₂—N(H)—R^(o),—S(O)₂—N(R^(o))—R^(o), —C(NH)—N(H)—R^(o), —C(NH)—N(R^(P))—R^(o),—N(H)—C(O)—R^(o), —N(H)—C(S)—R^(o), —N(R^(o))—C(O)—R^(o),—N(R^(o))—C(S)—R^(o), —N(H)—S(O)₂—R^(o), —N(R^(o))—S(O)₂—R^(o),—N(H)—C(O)—N(H)—R^(o), —N(H)—C(S)—N(H)—R^(o), —N(R^(o))—C(O)—NH₂,—N(R^(o))—C(S)—NH₂, —N(R^(o))—C(O)—N(H)—R^(o),—N(R^(o))—C(S)—N(H)—R^(o), —N(H)—C(O)—N(R^(o))—R^(o),—N(H)—C(S)—N(R^(o))—R^(o), —N(R^(o))—C(O)—N(R^(o))—R^(o),—N(R^(o))—C(S)—N(R^(o))—R^(o), —N(H)—S(O)₂—N(H)—R^(o),—N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), —R^(f), and —R^(g). It is understoodthat substitutions are chemically feasible and attached at any availableatom to provide a stable compound.

“Heteroaryl” alone or in combination refers to a monocyclic aromaticring structure containing 5 or 6 ring atoms, or a bicyclic aromaticgroup having 8 to 10 atoms, containing one or more, preferably 1-4, morepreferably 1-3, even more preferably 1-2, heteroatoms independentlyselected from the group consisting of O, S, and N. Heteroaryl is alsointended to include oxidized S or N, such as sulfinyl, sulfonyl andN-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is thepoint of attachment of the heteroaryl ring structure such that a stablecompound is produced. Examples of heteroaryl groups include, but are notlimited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl,benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl,pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl,isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl,triazolyl, furanyl, benzofuryl, and indolyl. “Nitrogen containingheteroaryl” refers to heteroaryl wherein at least one heteroatom is N.In some instances, for example when R groups of a nitrogen combine withthe nitrogen to form a 5 or 7 membered nitrogen containing heteroaryl,any heteroatoms in such 5 or 7 membered heteroaryl are N. An “optionallysubstituted heteroaryl” is a heteroaryl that is optionally independentlysubstituted, unless indicated otherwise, with one or more, preferably 1,2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any availableatom to produce a stable compound, wherein the substituents are selectedfrom the group consisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)—OH,—C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂,—N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(o), —S—R^(o),—O—C(O)—R^(o), —O—C(S)—R^(o), —C(O)—R^(o), —C(S)—R^(o), —C(O)—O—R^(o),—C(S)—O—R^(o), —S(O)—R^(o), —S(O)₂—R^(o), —C(O)—N(H)—R^(o),—C(S)—N(H)—R^(o), —C(O)—N(R^(o))—R^(o), —C(S)—N(R^(o))—R^(o),—S(O)₂—N(H)—R^(o), —S(O)₂—N(R^(o))—R^(o), —C(NH)—N(H)—R^(o),—C(NH)—N(R^(P))—R^(o), —N(H)—C(O)—R^(o), —N(H)—C(S)—R^(o),—N(R^(o))—C(O)—R^(o), —N(R^(o))—C(S)—R^(o), —N(H)—S(O)₂—R^(o),—N(R^(o))—S(O)₂—R^(o), —N(H)—C(O)—N(H)—R^(o), —N(H)—C(S)—N(H)—R^(o),—N(R^(o))—C(O)—NH₂, —N(R^(o))—C(S)—NH₂, —N(R^(o))—C(O)—N(H)—R^(o),—N(R^(o))—C(S)—N(H)—R^(o), —N(H)—C(O)—N(R^(o))—R^(o),—N(H)—C(S)—N(R^(o))—R^(o), —N(R^(o))—C(O)—N(R^(o))—R^(o),—N(R^(o))—C(S)—N(R^(o))—R^(o), —N(H)—S(O)₂—N(H)—R^(o),—N(R^(o))—S(O)₂—NH₂, —N(R^(o))—S(O)₂—N(H)—R^(o),—N(H)—S(O)₂—N(R^(o))—R^(o), —N(R^(o))—S(O)₂—N(R^(o))—R^(o), —N(H)—R^(o),—N(R^(o))—R^(o), —R^(d), —R^(e), —R^(f), and —R^(g). It is understoodthat substitutions are chemically feasible and attached at any availableatom to provide a stable compound.

The variables R^(o), R^(P), R, R^(d), R^(e), R^(f) and R^(g) as used inthe description of optional substituents for alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl and heteroaryl are defined asfollows:

-   each R^(o), R^(P), and R^(c) are independently selected from the    group consisting of R^(d), R^(e), R^(f), and R^(g), or R^(P) and    R^(c) combine with the nitrogen to which they are attached to form a    5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen    containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or    5 or 7 membered nitrogen containing heteroaryl are optionally    substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2,    or 3 substituents selected from the group consisting of halogen,    —NO₂, —CN, —OH, —NH₂, —O—R^(u), —S—R^(u), —N(H)—R^(u),    —N(R^(u))—R^(u), —R^(x), and —R^(y);-   each R^(d) is independently lower alkyl, wherein lower alkyl is    optionally substituted with one or more, preferably 1, 2, 3, 4 or 5,    also 1, 2 or 3 substituents selected from the group consisting of    fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂,    —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂,    —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(k), —S—R^(k), —O—C(O)—R^(k),    —O—C(S)—R^(k), —C(O)—R^(k), —C(S)—R^(k), —C(O)—O—R^(k),    —C(S)—O—R^(k), —S(O)—R^(k), —S(O)₂—R^(k), —C(O)—N(H)—R^(k),    —C(S)—N(H)—R^(k), —C(O)—N(R^(k))—R^(k), —C(S)—N(R^(k))—R^(k),    —S(O)₂—N(H)—R^(k), —S(O)₂—N(R^(k))—R^(k), —C(NH)—N(H)—R^(k),    —C(NH)—N(R^(m))—R^(n), —N(H)—C(O)—R^(k), —N(H)—C(S)—R^(k),    —N(R^(k))—C(O)—R^(k), —N(R^(k))—C(S)—R^(k), —N(H)—S(O)₂—R^(k),    —N(R^(k))—S(O)₂—R^(k), —N(H)—C(O)—N(H)—R^(k), —N(H)—C(S)—N(H)—R^(k),    —N(R^(k))—C(O)—NH₂, —N(R^(k))—C(S)—NH₂, —N(R^(k))—C(O)—N(H)—R^(k),    —N(R^(k))—C(S)—N(H)—R^(k), —N(H)—C(O)—N(R^(k))—R^(k),    —N(H)—C(S)—N(R^(o))—R^(k), —N(R^(k))—C(O)—N(R^(k))—R^(k),    —N(R^(k))—C(S)—N(R^(k))—R^(k), —N(H)—S(O)₂—N(H)—R^(k),    —N(R^(k))—S(O)₂—NH₂, —N(R^(k))—S(O)₂—N(H)—R^(k),    —N(H)—S(O)₂—N(R^(k))—R^(k), —N(R^(k))—S(O)₂—N(R^(k))—R^(k),    —N(H)—R^(k), —N(R^(k))—R^(k), —R^(i), and —R^(i);-   each R^(e) is independently lower alkenyl, wherein lower alkenyl is    optionally substituted with one or more, preferably 1, 2, 3, 4 or 5,    also 1, 2 or 3 substituents selected from the group consisting of    fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂,    —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂,    —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(k), —S—R^(k), —O—C(O)—R^(k),    —O—C(S)—R^(k), —C(O)—R^(k), —C(S)—R^(k), —C(O)—O—R^(k),    —C(S)—O—R^(k), —S(O)—R^(k), —S(O)₂—R^(k), —C(O)—N(H)—R^(k),    —C(S)—N(H)—R^(k), —C(O)—N(R^(k))—R^(k), —C(S)—N(R^(k))—R^(k),    —S(O)₂—N(H)—R^(k), —S(O)₂—N(R^(k))—R^(k), —C(NH)—N(H)—R^(k),    —C(NH)—N(R^(m))—R^(n), —N(H)—C(O)—R^(k), —N(H)—C(S)—R^(k),    —N(R^(k))—C(O)—R^(k), —N(R^(k))—C(S)—R^(k), —N(H)—S(O)₂—R^(k),    —N(R^(k))—S(O)₂—R^(k), —N(H)—C(O)—N(H)—R^(k), —N(H)—C(S)—N(H)—R^(k),    —N(R^(k))—C(O)—NH₂, —N(R^(k))—C(S)—NH₂, —N(R^(k))—C(O)—N(H)—R^(k),    —N(R^(k))—C(S)—N(H)—R^(k), —N(H)—C(O)—N(R^(k))—R^(k),    —N(H)—C(S)—N(R^(k))—R^(k), —N(R^(k))—C(O)—N(R^(k))—R^(k),    —N(R^(k))—C(S)—N(R^(k))—R^(k), —N(H)—S(O)₂—N(H)—R^(k),    —N(R^(k))—S(O)₂—NH₂, —N(R^(k))—S(O)₂—N(H)—R^(k),    —N(H)—S(O)₂—N(R^(k))—R^(k), —N(R^(k))—S(O)₂—N(R^(k))—R^(k),    —N(H)—R^(k), —N(R^(k))—R^(k), —R^(h), and —R;-   each R^(f) is independently lower alkynyl, wherein lower alkynyl is    optionally substituted with one or more, preferably 1, 2, 3, 4 or 5,    also 1, 2 or 3 substituents selected from the group consisting of    fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂,    —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂,    —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(k), —S—R^(k), —O—C(O)—R^(k),    —O—C(S)—R^(k), —C(O)—R^(k), —C(S)—R^(k), —C(O)—O—R^(k),    —C(S)—O—R^(k), —S(O)—R^(k), —S(O)₂—R^(k), —C(O)—N(H)—R^(k),    —C(S)—N(H)—R^(k), —C(O)—N(R^(k))—R^(k), —C(S)—N(R^(k))—R^(k),    —S(O)₂—N(H)—R^(k), —S(O)₂—N(R^(k))—R^(k), —C(NH)—N(H)—R^(k),    —C(NH)—N(R^(m))—R^(n), —N(H)—C(O)—R^(k), —N(H)—C(S)—R^(k),    —N(R^(k))—C(O)—R^(k), —N(R^(k))—C(S)—R^(k), —N(H)—S(O)₂—R^(k),    —N(R^(k))—S(O)₂—R^(k), —N(H)—C(O)—N(H)—R^(k), —N(H)—C(S)—N(H)—R^(k),    —N(R^(k))—C(O)—NH₂, —N(R^(k))—C(S)—NH₂, —N(R^(k))—C(O)—N(H)—R^(k),    —N(R^(k))—C(S)—N(H)—R^(k), —N(H)—C(O)—N(R^(k))—R^(k),    —N(H)—C(S)—N(R^(k))—R^(k), —N(R^(k))—C(O)—N(R^(k))—R^(k),    —N(R^(k))—C(S)—N(R^(k))—R^(k), —N(H)—S(O)₂—N(H)—R^(k),    —N(R^(k))—S(O)₂—NH₂, —N(R^(k))—S(O)₂—N(H)—R^(k),    —N(H)—S(O)₂—N(R^(k))—R^(k), —N(R^(k))—S(O)₂—N(R^(k))—R^(k),    —N(H)—R^(k), —N(R^(k))—R^(k), —R^(h), and —R^(j);-   each R^(g) is independently selected from the group consisting of    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally    substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2    or 3 substituents selected from the group consisting of halogen,    —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂, —C(S)—NH₂,    —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂,    —C(NH)—NH₂, —O—R^(k), —S—R^(k), —O—C(O)—R^(k), —O—C(S)—R^(k),    —C(O)—R^(k), —C(S)—R^(k), —C(O)—O—R^(k), —C(S)—O—R^(k), —S(O)—R^(k),    —S(O)₂—R^(k), —C(O)—N(H)—R^(k), —C(S)—N(H)—R^(k),    —C(O)—N(R^(k))—R^(k), —C(S)—N(R^(k))—R^(k), —S(O)₂—N(H)—R^(k),    —S(O)₂—N(R^(k))—R^(k), —C(NH)—N(H)—R^(k), —C(NH)—N(R^(m))—R^(n),    —N(H)—C(O)—R^(k), —N(H)—C(S)—R^(k), —N(R^(k))—C(O)—R^(k),    —N(R^(k))—C(S)—R^(k), —N(H)—S(O)₂—R^(k), —N(R^(k))—S(O)₂—R^(k),    —N(H)—C(O)—N(H)—R^(k), —N(H)—C(S)—N(H)—R^(k), —N(R^(k))—C(O)—NH₂,    —N(R^(k))—C(S)—NH₂, —N(R^(k))—C(O)—N(H)—R^(k),    —N(R^(k))—C(S)—N(H)—R^(k), —N(H)—C(O)—N(R^(k))—R^(k),    —N(H)—C(S)—N(R^(k))—R^(k), —N(R^(k))—C(O)—N(R^(k))—R^(k),    —N(R^(k))—C(S)—N(R^(k))—R^(k), —N(H)—S(O)₂—N(H)—R^(k),    —N(R^(k))—S(O)₂—NH₂, —N(R^(k))—S(O)₂—N(H)—R^(k),    —N(H)—S(O)₂—N(R^(k))—R^(k), —N(R^(k))—S(O)₂—N(R^(k))—R^(k),    —N(H)—R^(k), —N(R^(k))—R^(k), —R^(h), —R^(i), and —R^(j);    -   wherein R^(k), R^(m), and R^(n) at each occurrence are        independently selected from the group consisting of R^(h),        R^(i), and R^(j), or R^(m) and R^(n) combine with the nitrogen        to which they are attached to form a 5-7 membered        heterocycloalkyl or a 5 or 7 membered nitrogen containing        heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7        membered nitrogen containing heteroaryl are optionally        substituted with one or more, preferably 1, 2, 3, 4 or 5, also        1, 2, or 3 substituents selected from the group consisting of        halogen, —NO₂, —CN, —OH, —NH₂, O—R^(u), —S—R^(u), —N(H)—R^(u),        —NR^(u)R^(u), —R^(x), and —R^(y);    -   wherein each R^(h) is independently lower alkyl optionally        substituted with one or more, preferably 1, 2, 3, 4 or 5, also        1, 2, or 3 substituents selected from the group consisting of        fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂,        —C(S)—NH₂, —S(O)₂—NH₂, —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂,        —N(H)—S(O)₂—NH₂, —C(NH)—NH₂, —O—R^(r), —S—R^(r), —O—C(O)—R^(r),        —O—C(S)—R^(r), —C(O)—R^(r), —C(S)—R^(r), —C(O)—O—R^(r),        —C(S)—O—R^(r), —S(O)—R^(r), —S(O)₂—R^(r), —C(O)—N(H)—R^(r),        —C(S)—N(H)—R^(r), —C(O)—N(R^(r))—R^(r), —C(S)—N(R^(r))—R^(r),        —S(O)₂—N(H)—R^(r), —S(O)₂—N(R^(r))—R^(r), —C(NH)—N(H)—R^(r),        —C(NH)—N(R^(s))—R^(t), —N(H)—C(O)—R^(r), —N(H)—C(S)—R^(r),        —N(R^(r))—C(O)—R^(r), —N(R^(r))—C(S)—R^(r), —N(H)—S(O)₂—R^(r),        —N(R^(r))—S(O)₂—R^(r), —N(H)—C(O)—N(H)—R^(r),        —N(H)—C(S)—N(H)—R^(r), —N(R^(r))—C(O)—NH₂, —N(R^(r))—C(S)—NH₂,        —N(R^(r))—C(O)—N(H)—R^(o), —N(R^(r))—C(S)—N(H)—R^(o),        —N(H)—C(O)—N(R^(r))—R^(r), —N(H)—C(S)—N(O)R^(r),        —N(R^(r))—C(O)—N(R^(r))—R^(r), —N(R^(r))—C(S)—N(R^(r))—R^(r),        —N(H)—S(O)₂—N(H)—R^(r), —N(R^(r))—S(O)₂—NH₂,        —N(R^(r))—S(O)₂—N(H)—R^(r), —N(H)—S(O)₂—N(R^(r))—R^(r),        —N(R^(r))—S(O)₂—N(R^(r))—R^(r), —N(H)—R^(r), —N(R^(r))—, —R^(i),        and —R^(j);    -   wherein each R is independently selected from the group        consisting of lower alkenyl and lower alkynyl, wherein lower        alkenyl or lower alkynyl are optionally substituted with one or        more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents        selected from the group consisting of fluoro, —OH, —NH₂, —NO₂,        —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂,        —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂,        —O—R^(r), —S—R^(r), —O—C(O)—R^(r), —O—C(S)—R^(r), —C(O)—R^(r),        —C(S)—R^(r), —C(O)—O—R^(r), —C(S)—O—R^(r), —S(O)—R^(r),        —S(O)₂—R^(r), —C(O)—N(H)—R^(r), —C(S)—N(H)—R^(r),        —C(O)—N(R^(r))—R^(r), —C(S)—N(R^(r))—R^(r), —S(O)₂—N(H)—R^(r),        —S(O)₂—N(R^(r))—R^(r), —C(NH)—N(H)—R^(r), —C(NH)—N(R^(r))—R^(r),        —N(H)—C(O)—R^(r), —N(H)—C(S)—R^(r), —N(R^(r))—C(O)—R^(r),        —N(R^(r))—C(S)—R^(r), —N(H)—S(O)₂—R^(r), —N(R^(r))—S(O)₂—R^(r),        —N(H)—C(O)—N(H)—R^(r), —N(H)—C(S)—N(H)—R^(r),        —N(R^(r))—C(O)—NH₂, —N(R^(r))—C(S)—NH₂,        —N(R^(r))—C(O)—N(H)—R^(r), —N(R^(r))—C(S)—N(H)—R^(r),        —N(H)—C(O)—N(R^(r))—R^(r), —N(H)—C(S)—N(R^(r))—R^(r),        —N(R^(r))—C(O)—N(R^(r))—R^(r), —N(R^(r))—C(S)—N(R^(r))—R^(r),        —N(H)—S(O)₂—N(H)—, —N(R^(r))—S(O)₂—NH₂, —N(R^(r))—S(O)₂—N(H)—,        —N(H)—S(O)₂—N(R^(r))—R^(r), —N(R^(r))—S(O)₂—N(R^(r))—R^(r),        —N(H)—R^(r), —N(R^(r))—R^(r), and —R^(j);    -   wherein each R^(j) is independently selected from the group        consisting of cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl are optionally substituted with one or more,        preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected        from the group consisting of halogen, —OH, —NH₂, —NO₂, —CN,        —C(O)—OH, —C(S)—OH, —C(O)—NH₂, —C(S)—NH₂, —S(O)₂—NH₂,        —N(H)—C(O)—NH₂, —N(H)—C(S)—NH₂, —N(H)—S(O)₂—NH₂, —C(NH)—NH₂,        —O—R^(r), —S—R^(r), —O—C(O)—R^(r), —O—C(S)—R^(r), —C(O)—R^(r),        —C(S)—R^(r), —C(O)—O—R^(r), —C(S)—O—R^(r), —S(O)—R^(r),        —S(O)₂—R^(r), —C(O)—N(H)—R^(r), —C(S)—N(H)—R^(r),        —C(O)—N(R^(r))—R^(r), —C(S)—N(R^(r))—R^(r), —S(O)₂—N(H)—R^(r),        —S(O)₂—N(R^(r))—R^(r), —C(NH)—N(H)—R^(r), —C(NH)—N(R^(S))—R^(t),        —N(H)—C(O)—R^(r), —N(H)—C(S)—R^(r), —N(R^(r))—C(O)—R^(o),        —N(R^(r))—C(S)—R^(r), —N(H)—S(O)₂—R^(r), —N(R^(r))—S(O)₂—R^(r),        —N(H)—C(O)—N(H)—R^(r), —N(H)—C(S)—N(H)—R^(r),        —N(R^(r))—C(O)—NH₂, —N(R^(r))—C(S)—NH₂,        —N(R^(r))—C(O)—N(H)—R^(r), —N(R^(r))—C(S)—N(H)—R^(r),        —N(H)—C(O)—N(R^(r))—R^(r), —N(H)—C(S)—N(R^(r))—R^(r),        —N(R^(r))—C(O)—N(R^(r))—R^(r), —N(R^(r))—C(S)—N(R^(r))—R^(r),        —N(H)—S(O)₂—N(H)—R^(r), —N(R^(r))—S(O)₂—NH₂,        —N(R^(r))—S(O)₂—N(H)—R^(r), —N(H)—S(O)₂—N(R^(r))—R^(r),        —N(R^(r))—S(O)₂—N(R^(r))—R^(r), —N(H)—R^(r), —N(R^(r))—R^(r),        cycloalkylamino, and —R^(x);    -   wherein each R^(r), R^(s), and R^(t) at each occurrence are        independently selected from the group consisting of lower alkyl,        C₃₋₆ alkenyl, C₃₋₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl        and heteroaryl, wherein lower alkyl is optionally substituted        with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3        substituents selected from the group consisting of —R^(y),        fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein        C₃₋₆ alkenyl or C₃₋₆ alkynyl are optionally substituted with one        or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3        substituents selected from the group consisting of —R^(y),        fluoro, lower alkyl, fluoro substituted lower alkyl, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl,        and heteroaryl are optionally substituted with one or more,        preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents        selected from the group consisting of halogen, —OH, —NH₂, —NO₂,        —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, or R^(s) and R^(t) combine with the nitrogen to        which they are attached to form a 5-7 membered heterocycloalkyl        or a 5 or 7 membered nitrogen containing heteroaryl, wherein the        5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen        containing heteroaryl are optionally substituted with one or        more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents        selected from the group consisting of halogen, —NO₂, —CN, —OH,        —NH₂, O—R^(u), —S—R^(u), —N(H)—R^(u), —N(R^(u))—R^(u), —R^(x),        and —R^(y);    -   wherein each R^(u) is independently selected from the group        consisting of lower alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein        lower alkyl is optionally substituted with one or more,        preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents        selected from the group consisting of —R^(y), fluoro, —OH, —NH₂,        lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,        fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino, and wherein C₃₋₆ alkenyl or        C₃₋₆ alkynyl are optionally substituted with one or more,        preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents        selected from the group consisting of —R^(y), fluoro, —OH, —NH₂,        lower alkyl, fluoro substituted lower alkyl, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl,        and heteroaryl are optionally substituted with one or more,        preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents        selected from the group consisting of halogen, —OH, —NH₂, —NO₂,        —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino;    -   wherein each R^(x) is selected from the group consisting of        lower alkyl, lower alkenyl and lower alkynyl, wherein lower        alkyl is optionally substituted with one or more, preferably 1,        2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the        group consisting of —R^(y), fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, and wherein lower alkenyl or lower alkynyl are        optionally substituted with one or more, preferably 1, 2, 3, 4        or 5, also 1, 2, or 3 substituents selected from the group        consisting of —R^(y), fluoro, —OH, —NH₂, lower alkyl, fluoro        substituted lower alkyl, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   wherein each R^(y) is selected from the group consisting of        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are        optionally substituted with one or more, preferably 1, 2, 3, 4        or 5, also 1, 2, or 3 substituents selected from the group        consisting of halogen, —OH, —NH₂, —NO₂, —CN, lower alkyl, fluoro        substituted lower alkyl, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino, and cycloalkylamino.

In some embodiments, all occurrences of optionally substituted loweralkyl, optionally substituted lower alkenyl, optionally substituted C₃₋₆alkenyl, optionally substituted lower alkynyl, or optionally substitutedC₃₋₆ alkynyl are optionally substituted with one or more, also 1, 2 or 3groups or substituents selected from the group consisting of fluoro,—NO₂, —CN, —O—R^(1a), —S—R^(1a), —N(R^(1a))—R^(1a), —O—C(O)—R^(1a),—O—C(S)—R^(1a), —C(O)—R^(1a), —C(S)—R^(1a), —C(O)—O—R^(1a),—C(S)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a), —C(S)—N(R^(1a))—R^(1a),—S(O)₂—N(R^(1a))—R^(1a), —C(NH)—N(R^(1a))—R^(1a),—N(R^(1a))—C(O)—R^(1a), —N(R^(1a))—C(S)—R^(1a), —N(R^(1a))—S(O)₂—R^(a),—N(R^(1a))—C(O)—N(R^(1a))—R^(1a), —N(R^(1a))—C(S)—N(R^(1a))—R^(1a),—N(R^(1a))—S(O)₂—N(R^(1a))—R^(1a), —S(O)—R^(1a), —S(O)₂—R^(1a),cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more, also 1, 2 or 3 groups or substituents selected from thegroup consisting of halogen, —NO₂, —CN, —O—R^(1a), —S—R^(1a),—N(R^(1a))—R^(1a), —O—C(O)—R^(1a), —O—C(S)—R^(1a), —C(O)—R^(1a),—C(S)—R^(1a), —C(O)—O—R^(1a), —C(S)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a),—C(S)—N(R^(1a))—R^(1a), —S(O)₂—N(R^(1a))—R^(1a),—C(NH)—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a), —N(R^(1a))—C(S)—R^(1a),—N(R^(1a))—S(O)₂—R^(1a), —N(R^(1a))—C(O)—N(R^(1a))—R^(1a),—N(R^(1a))—C(S)—N(R^(1a))—R^(1a), —N(R^(1a))—S(O)₂—N(R^(1a))—R^(1a),—S(O)—R^(1a), —S(O)₂—R^(1a), —R^(1b), and lower alkyl optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino, and —R^(1b); and alloccurrences of optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted 5-7 membered heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted 5 or 7 membered nitrogen containing heteroarylare optionally substituted with one or more, also 1, 2, or 3 groups orsubstituents selected from the group consisting of halogen, —NO₂, —CN,—O—R^(1a), —S—R^(1a), —N(R^(1a))—R^(1a), —O—C(O)—R^(1a), —O—C(S)—R^(1a),—C(O)—R^(1a), —C(S)—R^(1a), —C(O)—O—R^(1a), —C(S)—O—R^(1a),—C(O)—N(R^(1a))—R^(1a), —C(S)—N(R^(1a))—R^(1a), —S(O)₂—N(R^(1a))—R^(1a),—C(NH)—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a), —N(R^(1a))—C(S)—R^(1a),—N(R^(1a))—S(O)₂—R^(1a), —N(R^(1a))—C(O)—N(R^(1a))—R^(1a),—N(R^(1a))—C(S)—N(R^(1a))—R^(1a), —N(R^(1a))—S(O)₂—N(R^(1a))—R^(1a),—S(O)—R^(1a), —S(O)₂—R^(1a), —R^(1b), and lower alkyl optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino, and —R^(1b); whereinR^(1a) is selected from the group consisting of hydrogen, —R^(1b), andlower alkyl optionally substituted with one or more, also 1, 2 or 3groups or substituents selected from the group consisting of fluoro,—OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, and —R^(1b), and wherein —R^(1b) is selected from thegroup consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of halogen, —CN, —OH, —NH₂, loweralkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino, andcycloalkylamino.

In some embodiments, all occurrences of optionally substituted loweralkyl, optionally substituted lower alkenyl, optionally substituted C₃₋₆alkenyl, optionally substituted lower alkynyl, or optionally substitutedC₃₋₆ alkynyl are optionally substituted with one or more, also 1, 2 or 3groups or substituents selected from the group consisting of fluoro,—CN, —O—R^(1a), —S—R^(1a), —N(R^(1a))—R^(1a), —C(O)—R^(1a),—C(S)—R^(1a), —C(O)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a),—C(S)—N(R^(1a))—R^(1a), —S(O)₂—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a),—N(R^(1a))—C(S)—R^(1a), —N(R^(1a))—S(O)₂—R^(1a), —S(O)—R^(1a),—S(O)₂—R^(1a), cycloalkyl, heterocycloalkyl, aryl and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of halogen, —CN, —O—R^(1a),—S—R^(1a), —N(R^(1a))—R^(1a), —C(O)—R^(1a), —C(S)—R^(1a),—C(O)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a), —C(S)—N(R^(1a))—R^(1a),—S(O)₂—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a), —N(R^(1a))—C(S)—R^(1a),—N(R^(1a))—S(O)₂—R^(1a), —S(O)—R^(1a), —S(O)₂—R^(1a), —R^(1b), and loweralkyl optionally substituted with one or more, also 1, 2 or 3 groups orsubstituents selected from the group consisting of fluoro, —OH, —NH₂,lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino, and—R^(1b); and all occurrences of optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted 5-7membered heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, or optionally substituted 5 or 7 memberednitrogen containing heteroaryl are optionally substituted with one ormore, also 1, 2, or 3 groups or substituents selected from the groupconsisting of halogen, —CN, —O—R^(1a), —S—R^(1a), —N(R^(1a))—R^(1a),—C(O)—R^(1a), —C(S)—R^(1a), —C(O)—O—R^(1a), —C(O)—N(R^(1a))—R^(1a),—C(S)—N(R^(1a))—R^(1a), —S(O)₂—N(R^(1a))—R^(1a), —N(R^(1a))—C(O)—R^(1a),—N(R^(1a))—C(S)—R^(1a), —N(R^(1a))—S(O)₂—R^(1a), —S(O)—R^(1a),—S(O)₂—R^(1a), —R^(1b), and lower alkyl optionally substituted with oneor more, also 1, 2 or 3 groups or substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino, and —R^(1b); wherein R^(1a) is selectedfrom the group consisting of hydrogen, —R^(1b), and lower alkyloptionally substituted with one or more, also 1, 2 or 3 groups orsubstituents selected from the group consisting of fluoro, —OH, —NH₂,lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino, and—R^(1b), and wherein —R^(1b) is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more, also 1, 2 or 3 groups or substituents selected from thegroup consisting of halogen, —CN, —OH, —NH₂, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, fluoro substituted loweralkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.

“Lower alkoxy” denotes the group —OR^(z), where R^(z) is lower alkyl.“Substituted lower alkoxy” denotes lower alkoxy in which R^(z) is loweralkyl substituted with one or more substituents as indicated herein, forexample, in the description of compounds of Formula I, includingdescriptions of substituted cycloalkyl, heterocycloalkyl, aryl andheteroaryl, attached at any available atom to provide a stable compound.Preferably, substitution of lower alkoxy is with 1, 2, 3, 4, or 5substituents, also 1, 2, or 3 substituents. For example “fluorosubstituted lower alkoxy” denotes lower alkoxy in which the lower alkylis substituted with one or more fluoro atoms, where preferably the loweralkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3fluoro atoms. It is understood that substitutions on alkoxy arechemically feasible and attached at any available atom to provide astable compound.

“Lower alkylthio” denotes the group —SR^(aa), where R^(aa) is loweralkyl. “Substituted lower alkylthio” denotes lower alkylthio in whichR^(aa) is lower alkyl substituted with one or more substituents asindicated herein, for example, in the description of compounds ofFormula I, including descriptions of substituted cycloalkyl,heterocycloalkyl, aryl and heteroaryl, attached at any available atom toprovide a stable compound. Preferably, substitution of lower alkylthiois with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. Forexample “fluoro substituted lower alkylthio” denotes lower alkylthio inwhich the lower alkyl is substituted with one or more fluoro atoms,where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood thatsubstitutions on alkylthio are chemically feasible and attached at anyavailable atom to provide a stable compound.

“Amino” or “amine” denotes the group —NH₂. “Mono-alkylamino” denotes thegroup —NHR^(bb) where R^(bb) is lower alkyl. “Di-alkylamino” denotes thegroup —NR^(bb)R^(cc), where R^(bb) and R^(cc) are independently loweralkyl. “Cycloalkylamino” denotes the group —NR^(dd)R^(ee), where R^(dd)and R^(ee) combine with the nitrogen to form a 5-7 memberedheterocycloalkyl, where the heterocycloalkyl may contain an additionalheteroatom within the ring, such as O, N, or S, and may also be furthersubstituted with lower alkyl. Examples of 5-7 membered heterocycloalkylinclude, but are not limited to, piperidine, piperazine,4-methylpiperazine, morpholine, and thiomorpholine. It is understoodthat when mono-alkylamino, di-alkylamino, or cycloalkylamino aresubstituents on other moieties, these are chemically feasible andattached at any available atom to provide a stable compound.

As used herein, the term “composition” refers to a formulation suitablefor administration to an intended animal subject for therapeuticpurposes that contains at least one pharmaceutically active compound andat least one pharmaceutically acceptable carrier or excipient.

The term “pharmaceutically acceptable” indicates that the indicatedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectables.

In the present context, the term “therapeutically effective” or“effective amount” indicates that the materials or amount of material iseffective to prevent, alleviate, or ameliorate one or more symptoms of adisease or medical condition, and/or to prolong the survival of thesubject being treated.

In the present context, the terms “synergistically effective” or“synergistic effect” indicate that two or more compounds that aretherapeutically effective, when used in combination, provide improvedtherapeutic effects greater than the additive effect that would beexpected based on the effect of each compound used by itself.

As used herein, the terms “ligand” and “modulator” are used equivalentlyto refer to a compound that changes (i.e., increases or decreases) theactivity of a target biomolecule, e.g., an enzyme such as a kinase. Theterm “inhibitor” refers to a modulator that decreases the activity ofthe target biomolecule. Generally a ligand or modulator will be a smallmolecule, where “small molecule refers to a compound with a molecularweight of 1500 daltons or less, or preferably 1000 daltons or less, 800daltons or less, or 600 daltons or less.

In the context of compounds binding to a target, the terms “greateraffinity” and “selective” indicates that the compound binds more tightlythan a reference compound, or than the same compound in a referencecondition, i.e., with a lower dissociation constant. In someembodiments, the greater affinity (i.e. selectivity) is at least 2, 3,4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-fold greateraffinity.

As used herein in connection with compounds of the invention, the term“synthesizing” and like terms means chemical synthesis from one or moreprecursor materials.

By “assaying” is meant the creation of experimental conditions and thegathering of data regarding a particular result of the experimentalconditions. For example, enzymes can be assayed based on their abilityto act upon a detectable substrate. A compound or ligand can be assayedbased on its ability to bind to a particular target molecule ormolecules.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with a particular biomolecule such as a protein kinase. Forexample, an agonist or antagonist of a particular biomolecule modulatesthe activity of that biomolecule, e.g., an enzyme, by either increasing(e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor)the activity of the biomolecule, such as an enzyme. Such activity istypically indicated in terms of an inhibitory concentration (IC₅₀) orexcitation concentration (EC₅₀) of the compound for an inhibitor oractivator, respectively, with respect to, for example, an enzyme.

In the context of the use, testing, or screening of compounds that areor may be modulators, the term “contacting” means that the compound(s)are caused to be in sufficient proximity to a particular molecule,complex, cell, tissue, organism, or other specified material thatpotential binding interactions and/or chemical reaction between thecompound and other specified material can occur.

As used herein in connection with amino acid or nucleic acid sequence,the term “isolate” indicates that the sequence is separated from atleast a portion of the amino acid and/or nucleic acid sequences withwhich it would normally be associated.

In connection with amino acid or nucleic sequences, the term “purified”indicates that the subject molecule constitutes a significantly greaterproportion of the biomolecules in a composition than the proportionobserved in a prior composition, e.g., in a cell culture. The greaterproportion can be 2-fold, 5-fold, 10-fold, or more than 10-fold, withrespect to the proportion found in the prior composition.

The present invention concerns compounds of Formula I, and allsub-generic formulae, that are modulators of protein kinases, forexample without limitation, the compounds are modulators of at least oneof the kinases selected from the group consisting of Abl, Akt1, Akt2,Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1,c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2,FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3α, Gsk3β, HCK,Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3,Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2,Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKCalpha, PKC beta, PKC theta, Plk1, Pyk2, Ret, ROCK1, ROCK2, Ron, Src,Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, and any mutationsthereof, and the use of such compounds in the treatment of diseases orconditions.

Kinase Targets and Indications of the Invention

Protein kinases play key roles in propagating biochemical signals indiverse biological pathways. More than 500 kinases have been described,and specific kinases have been implicated in a wide range of diseases orconditions (i.e., indications), including for example withoutlimitation, cancer, cardiovascular disease, inflammatory disease,neurological disease, and other diseases. As such, kinases representimportant control points for small molecule therapeutic intervention.Specific target protein kinases contemplated by the present inventionare described in the art, including, without limitation, protein kinasesas described in U.S. patent application Ser. No. 11/473,347 (see also,PCT publication WO2007002433), the disclosure of which is herebyincorporated by reference in its entirety, including all specifications,figures, and tables, and for all purposes, as well as the following:

A-Raf:

Target kinase A-Raf (i.e., v-raf murine sarcoma 3611 viral oncogenehomolog 1) is a 67.6 kDa serine/threonine kinase encoded by chromosomeXp11.4-p11.2 (symbol: ARAF). The mature protein comprises RBD (i.e., Rasbinding domain) and phorbol-ester/DAG-type zinc finger domain and isinvolved in the transduction of mitogenic signals from the cell membraneto the nucleus. A-Raf inhibitors may be useful in treating neurologicdiseases such as multi-infarct dementia, head injury, spinal cordinjury, Alzheimer's disease (AD), Parkinson's disease; neoplasticdiseases including, but not limited to, melanoma, glioma, sarcoma,carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal,ovarian), lymphoma (e.g. histiocytic lymphoma), neurofibromatosis,myelodysplastic syndrome, leukemia, tumor angiogenesis; pain ofneuropathic or inflammatory origin, including acute pain, chronic pain,cancer-related pain and migraine; and diseases associated with muscleregeneration or degeneration, including, but not limited to, vascularrestenosis, sarcopenia, muscular dystrophies (including, but not limitedto, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies),motor neuron diseases (including, but not limited to, amyotrophiclateral sclerosis, infantile progressive spinal muscular atrophy,intermediate spinal muscular atrophy, juvenile spinal muscular atrophy,spinal bulbar muscular atrophy, and adult spinal muscular atrophy),inflammatory myopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

B-Raf:

Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogene homologB1) is a 84.4 kDa serine/threonine kinase encoded by chromosome 7q34(symbol: BRAF). The mature protein comprises RBD (i.e., Ras bindingdomain), Cl (i.e., protein kinase C conserved region 1) and STK (i.e.,serine/threonine kinase) domains.

Target kinase B-Raf is involved in the transduction of mitogenic signalsfrom the cell membrane to the nucleus and may play a role in thepostsynaptic responses of hippocampal neurons. As such, genes of the RAFfamily encode kinases that are regulated by Ras and mediate cellularresponses to growth signals. Indeed, B-Raf kinase is a key component ofthe RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which plays afundamental role in the regulation of cell growth, division andproliferation, and, when constitutively activated, causes tumorigenesis.Among several isoforms of Raf kinase, the B-type, or B-Raf, is thestrongest activator of the downstream MAP kinase signaling.

The BRAF gene is frequently mutated in a variety of human tumors,especially in malignant melanoma and colon carcinoma. The most commonreported mutation was a missense thymine (T) to adenine (A) transversionat nucleotide 1796 (T1796A; amino acid change in the B-Raf protein isVal<600> to Glu<600>) observed in 80% of malignant melanoma tumors.Functional analysis reveals that this transversion is the only detectedmutation that causes constitutive activation of B-Raf kinase activity,independent of RAS activation, by converting B-Raf into a dominanttransforming protein. Based on precedents, human tumors developresistance to kinase inhibitors by mutating a specific amino acid in thecatalytic domain as the “gatekeeper”. (Balak, et. al., Clin Cancer Res.2006, 12:6494-501). Mutation of Thr-529 in BRAF to Ile is thusanticipated as a mechanism of resistance to BRAF inhibitors, and thiscan be envisioned as a transition in codon 529 from ACC to ATC.

Niihori et al., report that in 43 individuals withcardio-facio-cutaneous (CFC) syndrome, they identified two heterozygousKRAS mutations in three individuals and eight BRAF mutations in 16individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway isa common molecular basis for the three related disorders (Niihori etal., Nat Genet. 2006, 38(3):294-6).

c-Raf-1:

Target kinase c-Raf-1 (i.e., v-raf murine sarcoma viral oncogenehomolog 1) is a 73.0 kDa STK encoded by chromosome 3p25 (symbol: RAF1).c-Raf-1 can be targeted to to the mitochondria by BCL2 (i.e., oncogeneB-cell leukemia 2) which is a regulator of apoptotic cell death. Activec-Raf-1 improves BCL2-mediated resistance to apoptosis, and c-Raf-1phosphorylates BAD (i.e., BCL2-binding protein). c-Raf-1 is implicatedin carcinomas, including colorectal, ovarian, lung and renal cellcarcinoma. C-Raf-1 is also implicated as an important mediator of tumorangiogenesis (Hood, J. D. et al., 2002, Science 296, 2404). C-Raf-1inhibitors may also be useful for the treatment of acute myeloidleukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002,8(25):2243-8). Raf-1 activators may be useful as treatment forneuroendocrine tumors, such as medullary thyroid cancer, carcinoid,small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al.,Anticancer Drugs 2006, 17(2): 139-42).

Raf inhibitors (A-Raf and/or B-Raf and/or c-Raf-1) may be useful intreating A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease orcondition selected from the group consisting of neurologic diseases,including, but not limited to, multi-infarct dementia, head injury,spinal cord injury, Alzheimer's disease (AD), Parkinson's disease;neoplastic diseases including, but not limited to, melanoma, glioma,sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid,renal, ovarian), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis,acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumorangiogenesis, neuroendocrine tumors such as medullary thyroid cancer,carcinoid, small cell lung cancer and pheochromocytoma; pain ofneuropathic or inflammatory origin, including, but not limited to, acutepain, chronic pain, cancer-related pain, and migraine; cardiovasculardiseases, including, but not limited to, heart failure, ischemic stroke,cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathysyndromes), atherosclerosis, and reperfusion injury; inflammationincluding, but not limited to, psoriasis, arthritis and autoimmunediseases and conditions, osteoarthritis, endometriosis, scarring,vascular restenosis, fibrotic disorders, rheumatoid arthritis,inflammatory bowel disease (IBD); immunodeficiency diseases, including,but not limited to, organ transplant rejection, graft versus hostdisease; renal or prostatic diseases, including, but not limited to,diabetic nephropathy, polycystic kidney disease, nephrosclerosis,glomerulonephritis, prostate hyperplasia; metabolic disorders,including, but not limited to, obesity; infection, including, but notlimited to, Helicobacter pylori, Hepatitis and Influenza viruses, fever,and sepsis; pulmonary diseases, including, but not limited to, chronicobstructive pulmonary disease (COPD) and acute respiratory distresssyndrome (ARDS); genetic developmental diseases, including, but notlimited to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletalsyndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC), andneural crest syndrome abnormalities causing cardiovascular, skeletal,intestinal, skin, hair and endocrine diseases.

Kinase Activity Assays

A number of different assays for kinase activity can be utilized forassaying for active modulators and/or determining specificity of amodulator for a particular kinase or group or kinases. In addition tothe assay mentioned in the Examples below, one of ordinary skill in theart will know of other assays that can be utilized and can modify anassay for a particular application. For example, numerous papersconcerning kinases describe assays that can be used.

Additional alternative assays can employ binding determinations. Forexample, this sort of assay can be formatted either in a fluorescenceresonance energy transfer (FRET) format, or using an AlphaScreen(amplified luminescent proximity homogeneous assay) format by varyingthe donor and acceptor reagents that are attached to streptavidin or thephosphor-specific antibody.

Organic Synthetic Techniques

A wide array of organic synthetic techniques exist in the art tofacilitate the construction of potential modulators. Many of theseorganic synthetic methods are described in detail in standard referencesources utilized by those skilled in the art. One example of such areference is March, 1994, Advanced Organic Chemistry; Reactions,Mechanisms and Structure, New York, McGraw Hill. Thus, the techniquesuseful to synthesize a potential modulator of kinase function arereadily available to those skilled in the art of organic chemicalsynthesis.

Alternative Compound Forms or Derivatives

Compounds contemplated herein are described with reference to bothgeneric formulae and specific compounds. In addition, inventioncompounds may exist in a number of different forms or derivatives, allwithin the scope of the present invention. Alternative forms orderivatives, include, for example, (a) prodrugs, and active metabolites(b) tautomers, isomers (including stereoisomers and regioisomers), andracemic mixtures (c) pharmaceutically acceptable salts and formulationsand (d) solid forms, including different crystal forms, polymorphic oramorphous solids, including hydrates and solvates thereof, and otherforms.

(a) Prodrugs and Metabolites

In addition to the present formulae and compounds described herein, theinvention also includes prodrugs (generally pharmaceutically acceptableprodrugs), active metabolic derivatives (active metabolites), and theirpharmaceutically acceptable salts.

Prodrugs are compounds or pharmaceutically acceptable salts thereofwhich, when metabolized under physiological conditions or when convertedby solvolysis, yield the desired active compound. Prodrugs include,without limitation, esters, amides, carbamates, carbonates, ureides,solvates, or hydrates of the active compound. Typically, the prodrug isinactive, or less active than the active compound, but may provide oneor more advantageous handling, administration, and/or metabolicproperties. For example, some prodrugs are esters of the activecompound; during metabolysis, the ester group is cleaved to yield theactive drug. Esters include, for example, esters of a carboxylic acidgroup, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenolgroups. In this context, a common example is an alkyl ester of acarboxylic acid. Some prodrugs are activated enzymatically to yield theactive compound, or a compound which, upon further chemical reaction,yields the active compound. Prodrugs may proceed from prodrug form toactive form in a single step or may have one or more intermediate formswhich may themselves have activity or may be inactive.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can beconceptually divided into two non-exclusive categories, bioprecursorprodrugs and carrier prodrugs. Generally, bioprecursor prodrugs arecompounds that are inactive or have low activity compared to thecorresponding active drug compound, that contain one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollow types:

Oxidative Reactions:

Oxidative reactions are exemplified without limitation to reactions suchas oxidation of alcohol, carbonyl, and acid functionalities,hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbonatoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbondouble bonds, oxidation of nitrogen-containing functional groups,oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative O- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

Reductive Reactions:

Reductive reactions are exemplified without limitation to reactions suchas reduction of carbonyl functionalities, reduction of alcoholfunctionalities and carbon-carbon double bonds, reduction ofnitrogen-containing functional groups, and other reduction reactions.

Reactions without Change in the Oxidation State:

Reactions without change in the state of oxidation are exemplifiedwithout limitation to reactions such as hydrolysis of esters and ethers,hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavageof non-aromatic heterocycles, hydration and dehydration at multiplebonds, new atomic linkages resulting from dehydration reactions,hydrolytic dehalogenation, removal of hydrogen halide molecule, andother such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improves uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, the prodrug and anyrelease transport moiety are acceptably non-toxic. For prodrugs wherethe transport moiety is intended to enhance uptake, typically therelease of the transport moiety should be rapid. In other cases, it isdesirable to utilize a moiety that provides slow release, e.g., certainpolymers or other moieties, such as cyclodextrins. (See, e.g., Cheng etal., U.S. Patent Publ. No. 20040077595, application Ser. No. 10/656,838,incorporated herein by reference.) Such carrier prodrugs are oftenadvantageous for orally administered drugs. In some instances, thetransport moiety provides targeted delivery of the drug, for example thedrug maybe conjugated to an antibody or antibody fragment. Carrierprodrugs can, for example, be used to improve one or more of thefollowing properties: increased lipophilicity, increased duration ofpharmacological effects, increased site-specificity, decreased toxicityand adverse reactions, and/or improvement in drug formulation (e.g.,stability, water solubility, suppression of an undesirable organolepticor physiochemical property). For example, lipophilicity can be increasedby esterification of hydroxyl groups with lipophilic carboxylic acids,or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols.Wermuth, supra.

Metabolites, e.g., active metabolites, overlap with prodrugs asdescribed above, e.g., bioprecursor prodrugs. Thus, such metabolites arepharmacologically active compounds or compounds that further metabolizeto pharmacologically active compounds that are derivatives resultingfrom metabolic processes in the body of a subject. Of these, activemetabolites are such pharmacologically active derivative compounds. Forprodrugs, the prodrug compound is generally inactive or of loweractivity than the metabolic product. For active metabolites, the parentcompound may be either an active compound or may be an inactive prodrug.For example, in some compounds, one or more alkoxy groups can bemetabolized to hydroxyl groups while retaining pharmacologic activityand/or carboxyl groups can be esterified, e.g., glucuronidation. In somecases, there can be more than one metabolite, where an intermediatemetabolite(s) is further metabolized to provide an active metabolite.For example, in some cases a derivative compound resulting frommetabolic glucuronidation may be inactive or of low activity, and can befurther metabolized to provide an active metabolite.

Metabolites of a compound may be identified using routine techniquesknown in the art, and their activities determined using tests such asthose described herein. See, e.g., Bertolini et al., 1997, J. Med.Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757;Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.

(b) Tautomers, Stereoisomers, and Regioisomers

It is understood that some compounds may exhibit tautomerism. In suchcases, the formulae provided herein expressly depict only one of thepossible tautomeric forms. It is therefore to be understood that theformulae provided herein are intended to represent any tautomeric formof the depicted compounds and are not to be limited merely to thespecific tautomeric form depicted by the drawings of the formulae.

Likewise, some of the compounds according to the present invention mayexist as stereoisomers, i.e. having the same atomic connectivity ofcovalently bonded atoms yet differing in the spatial orientation of theatoms. For example, compounds may be optical stereoisomers, whichcontain one or more chiral centers, and therefore, may exist in two ormore stereoisomeric forms (e.g. enantiomers or diastereomers). Thus,such compounds may be present as single stereoisomers (i.e., essentiallyfree of other stereoisomers), racemates, and/or mixtures of enantiomersand/or diastereomers. As another example, stereoisomers includegeometric isomers, such as cis- or trans-orientation of substituents onadjacent carbons of a double bond. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthe present invention. Unless specified to the contrary, all suchstereoisomeric forms are included within the formulae provided herein.

In some embodiments, a chiral compound of the present invention is in aform that contains at least 80% of a single isomer (60% enantiomericexcess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70%e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5%(95% e.e. or d.e.), or 99% (98% e.e. or d.e.). As generally understoodby those skilled in the art, an optically pure compound having onechiral center is one that consists essentially of one of the twopossible enantiomers (i.e., is enantiomerically pure), and an opticallypure compound having more than one chiral center is one that is bothdiastereomerically pure and enantiomerically pure. In some embodiments,the compound is present in optically pure form, such optically pure formbeing prepared and/or isolated by methods known in the art (e.g. byrecrystallization techniques, chiral synthetic techniques (includingsynthesis from optically pure starting materials), and chromatographicseparation using a chiral column.

(c) Pharmaceutically Acceptable Salts and Formulations

Unless specified to the contrary, specification of a compound hereinincludes pharmaceutically acceptable salts of such compound. Thus,compounds of Formula I can be in the form of pharmaceutically acceptablesalts, or can be formulated as pharmaceutically acceptable salts.Contemplated pharmaceutically acceptable salt forms include, withoutlimitation, mono, bis, tris, tetrakis, and so on. Pharmaceuticallyacceptable salts are non-toxic in the amounts and concentrations atwhich they are administered. The preparation of such salts canfacilitate the pharmacological use by altering the physicalcharacteristics of a compound without preventing it from exerting itsphysiological effect. Useful alterations in physical properties includelowering the melting point to facilitate transmucosal administration andincreasing the solubility to facilitate administering higherconcentrations of the drug. A compound of the invention may possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic or organicbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt.

Pharmaceutically acceptable salts include acid addition salts such asthose containing chloride, bromide, iodide, hydrochloride, acetate,phenylacetate, acrylate, ascorbate, aspartate, benzoate,2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate,hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate,citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate,glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate,isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate,lactate, malate, maleate, hydroxymaleate, methylmaleate, malonate,mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate,oxalate, pamoate, phosphate, monohydrogenphosphate, dihydrogenphosphate,orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate,3-phosphoglycerate, phthalate, propionate, phenylpropionate, propiolate,pyruvate, quinate, salicylate, 4-aminosalicylate, sebacate, stearate,suberate, succinate, sulfate, pyrosulfate, bisulfate, sulfite,bisulfite, sulfamate, sulfonate, benzenesulfonate (i.e. besylate),ethanesulfonate (i.e. esylate), ethane-1,2-disulfonate,2-hydroxyethanesulfonate (i.e. isethionate), methanesulfonate (i.e.mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e.napsylate), propanesulfonate, p-toluenesulfonate (i.e. tosylate),xylenesulfonates, cyclohexylsulfamate, tartrate, and trifluoroacetate.These pharmaceutically acceptable acid addition salts can be preparedusing the appropriate corresponding acid.

When acidic functional groups, such as carboxylic acid or phenol arepresent, pharmaceutically acceptable salts also include basic additionsalts such as those containing benzathine, chloroprocaine, choline,ethanolamine, diethanolamine, triethanolamine, t-butylamine,dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine,meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine,procaine, aluminum, calcium, copper, iron, lithium, magnesium,manganese, potassium, sodium, zinc, ammonium, and mono-, di-, ortri-alkylamines, or salts derived from amino acids such as L-histidine,L-glycine, L-lysine, and L-arginine. For example, see Remington'sPharmaceutical Sciences, 19^(th) ed., Mack Publishing Co., Easton, Pa.,Vol. 2, p. 1457, 1995. These pharmaceutically acceptable base additionsalts can be prepared using the appropriate corresponding base.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent. If the particularcompound is an acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an appropriate inorganic or organic base.

The pharmaceutically acceptable salt of the different compounds may bepresent as a complex. Examples of complexes include 8-chlorotheophyllinecomplex (analogous to, e.g., dimenhydrinate: diphenhydramine8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrininclusion complexes.

(d) Other Compound Forms

In the case of agents that are solids, it is understood by those skilledin the art that the compounds and salts may exist in different crystalor polymorphic forms, or may be formulated as co-crystals, or may be inan amorphous form, or may be any combination thereof (e.g. partiallycrystalline, partially amorphous, or mixtures of polymorphs) all ofwhich are intended to be within the scope of the present invention andspecified formulae. Whereas salts are formed by acid/base addition, i.e.a free base or free acid of the compound of interest forms an acid/basereaction with a corresponding addition base or addition acid,respectively, resulting in an ionic charge interaction, co-crystals area new chemical species that is formed between neutral compounds,resulting in the compound and an additional molecular species in thesame crystal structure.

Additionally, the formulae are intended to cover hydrated or solvated aswell as unhydrated or unsolvated forms of the identified structures. Forexample, the indicated structures include both hydrated and non-hydratedforms. Other examples of solvates include the structures in combinationwith a suitable solvent, such as isopropanol, ethanol, methanol,dimethylsulfoxide, ethyl acetate, acetic acid, or ethanolamine.

Administration

The methods and compounds will typically be used in therapy for humansubjects. However, they may also be used to treat similar or identicalindications in other animal subjects. Compounds of Formula I can beadministered by different routes, including injection (i.e. parenteral,including intravenous, intraperitoneal, subcutaneous, andintramuscular), oral, transdermal, transmucosal, rectal, or inhalant.Such dosage forms should allow the compound to reach target cells. Otherfactors are well known in the art, and include considerations such astoxicity and dosage forms that retard the compound or composition fromexerting its effects. Techniques and formulations generally may be foundin Remington: The Science and Practice of Pharmacy, 21^(st) edition,Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (herebyincorporated by reference herein).

In some embodiments, compositions will comprise carriers or excipients,which may be chosen to facilitate administration of the compound by aparticular route. Examples of carriers include calcium carbonate,calcium phosphate, various sugars such as lactose, glucose, or sucrose,types of starch, cellulose derivatives, gelatin, lipids, liposomes,nanoparticles, and the like. Carriers also include physiologicallycompatible liquids as solvents or for suspensions, including, forexample, sterile solutions of water for injection (WFI), salinesolution, dextrose solution, Hank's solution, Ringer's solution,vegetable oils, mineral oils, animal oils, polyethylene glycols, liquidparaffin, and the like.

In some embodiments, oral administration may be used. Pharmaceuticalpreparations for oral use can be formulated into conventional oraldosage forms such as capsules, tablets, and liquid preparations such assyrups, elixirs, and concentrated drops. Compounds of Formula I may becombined with solid excipients, optionally grinding a resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain, for example, tablets, coatedtablets, hard capsules, soft capsules, solutions (e.g. aqueous,alcoholic, or oily solutions) and the like. Suitable excipients are, inparticular, fillers such as sugars, including lactose, glucose, sucrose,mannitol, or sorbitol; cellulose preparations, for example, corn starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP:povidone); oily excipients, including vegetable and animal oils, such assunflower oil, olive oil, or codliver oil. The oral dosage formulationsmay also contain disintegrating agents, such as the cross-linkedpolyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such assodium alginate; a lubricant, such as talc or magnesium stearate; aplasticizer, such as glycerol or sorbitol; a sweetening such as sucrose,fructose, lactose, or aspartame; a natural or artificial flavoringagent, such as peppermint, oil of wintergreen, or cherry flavoring; ordye-stuffs or pigments, which may be used for identification orcharacterization of different doses or combinations. Also provided aredragee cores with suitable coatings. For this purpose, concentratedsugar solutions may be used, which may optionally contain, for example,gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols.

In some embodiments, injection (parenteral administration) may be used,e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous.Compounds of Formula I for injection may be formulated in sterile liquidsolutions, preferably in physiologically compatible buffers orsolutions, such as saline solution, Hank's solution, or Ringer'ssolution. Dispersions may also be prepared in non-aqueous solutions,such as glycerol, propylene glycol, ethanol, liquid polyethyleneglycols, triacetin, and vegetable oils. Solutions may also contain apreservative, such as methylparaben, propylparaben, chlorobutanol,phenol, sorbic acid, thimerosal, and the like. In addition, thecompounds may be formulated in solid form, including, for example,lyophilized forms, and redissolved or suspended prior to use.

In some embodiments, transmucosal, topical or transdermal administrationmay be used. In such formulations of compounds of Formula I, penetrantsappropriate to the barrier to be permeated are used. Such penetrants aregenerally known in the art, and include, for example, for transmucosaladministration, bile salts and fusidic acid derivatives. In addition,detergents may be used to facilitate permeation. Transmucosaladministration, for example, may be through nasal sprays orsuppositories (rectal or vaginal). Compositions of compounds of FormulaI for topical administration may be formulated as oils, creams, lotions,ointments, and the like by choice of appropriate carriers known in theart. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). In someembodiments, carriers are selected such that the active ingredient issoluble. Emulsifiers, stabilizers, humectants and antioxidants may alsobe included as well as agents imparting color or fragrance, if desired.Creams for topical application are preferably formulated from a mixtureof mineral oil, self-emulsifying beeswax and water in which mixture theactive ingredient, dissolved in a small amount of solvent (e.g., anoil), is admixed. Additionally, administration by transdermal means maycomprise a transdermal patch or dressing such as a bandage impregnatedwith an active ingredient and optionally one or more carriers ordiluents known in the art. To be administered in the form of atransdermal delivery system, the dosage administration will becontinuous rather than intermittent throughout the dosage regimen.

In some embodiments, compounds are administered as inhalants. Compoundsof Formula I may be formulated as dry powder or a suitable solution,suspension, or aerosol. Powders and solutions may be formulated withsuitable additives known in the art. For example, powders may include asuitable powder base such as lactose or starch, and solutions maycomprise propylene glycol, sterile water, ethanol, sodium chloride andother additives, such as acid, alkali and buffer salts. Such solutionsor suspensions may be administered by inhaling via spray, pump,atomizer, or nebulizer, and the like. The compounds of Formula I mayalso be used in combination with other inhaled therapies, for examplecorticosteroids such as fluticasone proprionate, beclomethasonedipropionate, triamcinolone acetonide, budesonide, and mometasonefuroate; beta agonists such as albuterol, salmeterol, and formoterol;anticholinergic agents such as ipratroprium bromide or tiotropium;vasodilators such as treprostinal and iloprost; enzymes such as DNAase;therapeutic proteins; immunoglobulin antibodies; an oligonucleotide,such as single or double stranded DNA or RNA, siRNA; antibiotics such astobramycin; muscarinic receptor antagonists; leukotriene antagonists;cytokine antagonists; protease inhibitors; cromolyn sodium; nedocrilsodium; and sodium cromoglycate.

The amounts of various compounds to be administered can be determined bystandard procedures taking into account factors such as the compoundactivity (in vitro, e.g. the compound IC₅₀ vs. target, or in vivoactivity in animal efficacy models), pharmacokinetic results in animalmodels (e.g. biological half-life or bioavailability), the age, size,and weight of the subject, and the disorder associated with the subject.The importance of these and other factors are well known to those ofordinary skill in the art. Generally, a dose will be in the range ofabout 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject beingtreated. Multiple doses may be used.

The compounds of Formula I may also be used in combination with othertherapies for treating the same disease. Such combination use includesadministration of the compounds and one or more other therapeutics atdifferent times, or co-administration of the compound and one or moreother therapies. In some embodiments, dosage may be modified for one ormore of the compounds of the invention or other therapeutics used incombination, e.g., reduction in the amount dosed relative to a compoundor therapy used alone, by methods well known to those of ordinary skillin the art.

It is understood that use in combination includes use with othertherapies, drugs, medical procedures etc., where the other therapy orprocedure may be administered at different times (e.g. within a shorttime, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within alonger time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than acompound of Formula I, or at the same time as a compound of Formula I.Use in combination also includes use with a therapy or medical procedurethat is administered once or infrequently, such as surgery, along with acompound of Formula I administered within a short time or longer timebefore or after the other therapy or procedure. In some embodiments, thepresent invention provides for delivery of a compound of Formula I andone or more other drug therapeutics delivered by a different route ofadministration or by the same route of administration. The use incombination for any route of administration includes delivery of acompound of Formula I and one or more other drug therapeutics deliveredby the same route of administration together in any formulation,including formulations where the two compounds are chemically linked insuch a way that they maintain their therapeutic activity whenadministered. In one aspect, the other drug therapy may beco-administered with a compound of Formula I. Use in combination byco-administration includes administration of co-formulations orformulations of chemically joined compounds, or administration of two ormore compounds in separate formulations within a short time of eachother (e.g. within an hour, 2 hours, 3 hours, up to 24 hours),administered by the same or different routes. Co-administration ofseparate formulations includes co-administration by delivery via onedevice, for example the same inhalant device, the same syringe, etc., oradministration from separate devices within a short time of each other.Co-formulations of a compound of Formula I and one or more additionaldrug therapies delivered by the same route includes preparation of thematerials together such that they can be administered by one device,including the separate compounds combined in one formulation, orcompounds that are modified such that they are chemically joined, yetstill maintain their biological activity. Such chemically joinedcompounds may have a linkage that is substantially maintained in vivo,or the linkage may break down in vivo, separating the two activecomponents.

EXAMPLES

Examples related to the present invention are described below. In mostcases, alternative techniques can be used. The examples are intended tobe illustrative and are not limiting or restrictive to the scope of theinvention. In some examples, the mass spectrometry result indicated fora compound may have more than one value due to the isotope distributionof an atom in the molecule, such as a compound having a bromo or chlorosubstituent.

Unless specifically indicated otherwise, the Formula enumeration and Rgroup enumeration used in the following examples is not related to suchenumeration in other sections of this application. The reagents andsolvents used in these examples can be readily substituted withappropriate alternatives as are known in the art and isolation ofproducts is readily achieved by methods known in the art, including, butnot limited to, extraction, crystallization, and chromatographicmethods.

Example 1: Synthesis of Compound of Formula Ib or Id Wherein A is —C(O)—

Compounds of Formula Ib or Id, as defined in paragraphs [0010] and[0016], respectively, wherein A is —C(O)—, can be prepared in five stepsas described in Scheme 1.

Step 1—Synthesis of Compound 2

Compound 1 (R² and R⁴ as defined in paragraph [0004]) is dissolved in ananhydrous solvent (e.g. tetrahydrofuran) under nitrogen atmosphere. Thesolution is cooled down with the aid of a dry ice and acetone bath. Tothis solution is added a base (e.g. n-butyllithium), followed by1,2-bis(chlorodimethylsilyl)ethane at low temperature (typically below−70° C.). The resulting mixture is stirred at low temperature for 1-2hours. To this solution is added a base (e.g. n-butyllithium), followedby ethyl chloroformate. The resulting mixture is allowed to warm to roomtemperature and then stirred at room temperature for 1-3 days. Thereaction mixture is quenched by an acid solution, stirred at roomtemperature for a couple of hours, and then basified. The mixture isextracted with an organic solvent (e.g. dichloromethane or ethylacetate). The desired compound 2 is purified by chromatography.

Step 2—Synthesis of Compound 3

To compound 2 in an organic solvent (e.g. dichloromethane) is addedpyridine, followed by an appropriate acylating agent, isocyanate, orsulfonyl chloride such as propane-1-sulfonylchloride. The reactionmixture is stirred at room temperature for over 12 hours and the mixtureis then poured into water. The organic layer is separated and theaqueous layer is extracted with an appropriate organic solvent (e.g.dichloromethane). The desired compound 3 (L₂ and R³ as defined inparagraph [0005], or L₂ is S(O)₂ for Formula Ib) is purified bychromatography.

Step 3—Synthesis of Compound 4

To compound 3 in a solvent mixture (e.g. tetrahydrofuran and water) isadded a base (e.g. lithium hydroxide or sodium hydroxide). The resultingsuspension is stirred in a heated oil bath for over 10 hours. Thereaction mixture is cooled down to room temperature and then acidifiedwith an acid solution such as concentrated hydrochloric acid. Theaqueous layer is separated and extracted with an appropriate organicsolvent (e.g. ethyl acetate). The desired compound 4 is purified bychromatography.

Step 4—Synthesis of Compound 5

To a suspension of compound 4 in an anhydrous solvent (e.g.dichloromethane), cooled with an ice and water bath, oxalyl chloride isadded slowly, followed by dimethylformamide. The reaction mixture isstirred at room temperature for a few hours. After removal of thesolvent and excess oxalyl chloride, the residue is used in the next stepwithout further purification.

Step 5—Synthesis of Compound of Formula Ib or Id

To an appropriate amine 6 (Ar, m, R¹ and R¹¹ as defined in paragraph[0005]) in an anhydrous solvent (e.g. tetrahydrofuran) is added a base(e.g. triethylamine). To this mixture, cooled with an ice and salt bath,a solution of compound 5 in an anhydrous solvent (e.g. tetrahydrofuran)is added slowly. The resulting mixture was stirred at room temperaturefor over 12 hours. The desired compound of Formula Ib (L₂ is S(O)₂) orId is purified by chromatography.

Example 2: Synthesis of Compound of Formula Ic or Ie

Compounds of Formula Ic or Ie, as defined in paragraphs [0015] and[0021], respectively, can be prepared in four steps as described inScheme 2.

Step 1—Synthesis of Compound 8

Compound 7 (R² as defined in paragraph [0005]) is dissolved in anappropriate solvent (e.g. methanol). To this solution is added catalyst(e.g. palladium on carbon). The suspension is then placed under ahydrogen atmosphere and shaken at room temperature for over 12 hours.The catalyst is removed by filtration on a pad of celite and washed withan appropriate solvent (e.g. methanol). The filtrate is concentratedunder reduced pressure to give compound 8, which is used in the nextstep without further purification.

Step 2—Synthesis of Compound 9

To compound 8 in an organic solvent (e.g. dichloromethane) is added abase (e.g. pyridine) followed by an appropriate acylating agent,isocyanate, or sulfonyl chloride. The reaction mixture is stirred atroom temperature for over 12 hours. The reaction mixture is then pouredinto water. The organic layer is collected and the aqueous layer isextracted with an appropriate organic solvent (e.g. dichloromethane).The organic solvents are then combined. The desired compound 9 (L₂ andR³ as defined in paragraph [0005], or L₂ is S(O)₂ for Formula Ic) ispurified by chromatography.

Step 3—Synthesis of Compound 10

To compound 9 in an organic solvent (e.g. tetrahydrofuran ordichloromethane) is added a base (e.g. sodium hydride) at lowtemperature, followed by an appropriate alkylating agent (e.g. halide).The reaction mixture is stirred at room temperature or heated in an oilbath as necessary, for a few hours. The reaction mixture is then pouredinto water. The organic layer is collected and the aqueous layer isextracted with an appropriate organic solvent (e.g. ethyl acetate ordichloromethane). The organic solvents are then combined. The desiredcompound 10 (R⁴ as defined in paragraph [0005]) is purified bychromatography.

Step 4—Synthesis of Compound of Formula Ic or Ie

A mixture of compound 10, an appropriate boronic acid 11 (Ar, m and R¹as defined in paragraph [0004]), and a catalyst (e.g.tetrakis(triphenylphosphine)palladium) in a mixture of base (e.g.aqueous solution of potassium carbonate) and an appropriate organicsolvent (e.g. acetonitrile) is heated in an oil bath or is irradiated ina microwave system at over 100° C. for an appropriate time depending onstarting materials. The reaction mixture is poured into water and thenextracted with an appropriate organic solvent (e.g. dichloromethane orethyl acetate). The organic solvents are then combined. The desiredcompound of Formula Ic (L₂ is S(O)₂) or Id is purified bychromatography.

Example 3: Synthesis of Compound of Formula I where L₁ is —CH₂NR¹¹—

Compounds of Formula I, as defined in paragraph [0005] where L₁ is—CH₂NR¹¹—, can be prepared in three steps as described in Scheme3—Method A, or one step as described in Scheme 3—Method B.

Step 1—Synthesis of Compound 12

Compound 4 (prepared as described in Scheme 1, Step 3 in Example 1) isdissolved in an appropriate solvent (e.g. tetrahydrofuran). To thissolution is added an appropriate reducing agent (e.g. lithiumtetrahydroaluminate) at low temperature (typically below −30° C.). Thereaction mixture is then stirred at room temperature for 2-24 hours.Sodium sulfate is added and the mixture is stirred at room temperaturefor 30 minutes. The mixture is filtered through a pad of celite andwashed with an appropriate solvent (e.g. ethyl acetate). The filtrate isconcentrated under reduced pressure to give compound 12, which is usedin the next step without further purification.

Step 2—Synthesis of Compound 13

Compound 13 (LG is a suitable leaving group) is prepared by convertingcompound 12 into a mesylate or triflate by reacting with thecorresponding sulfonyl chloride in an appropriate organic solvent. Itcan also be converted into the corresponding bromide by reacting with anappropriate agent (e.g. phosphorous tribromide) in the presence of anappropriate base (e.g. pyridine).

Step 3—Synthesis of Compound of Formula I where L₁ is —CH₂NR¹¹—

To a mixture of compound 13 and a base (e.g. cesium carbonate) in anappropriate organic solvent (e.g. acetonitrile), amine 6 is added. Thereaction mixture is stirred at room temperature, or heated in an oilbath if necessary, for 2-24 hours. The reaction mixture is poured intowater and then extracted with an appropriate organic solvent (e.g.dichloromethane or ethyl acetate). The organic solvents are thencombined. The desired compound of Formula I is purified bychromatography.

Step 1—Preparation of Compound 63

To substituted phenylamine 1 (R² and R⁴ as defined in paragraph [0005])in an appropriate solvent (e.g. tetrahydrofuran) are added a base (e.g.triethylamine) and acid halide (e.g. acid chloride or sulfonyl chloride)in an appropriate organic solvent under an atmosphere of nitrogen. Thereaction is stirred at room temperature for 2-24 hours. The reactionmixture is then poured into an acid solution and extracted with anappropriate organic solvent (e.g. dichloromethane or ethyl acetate). Theorganic layers are combined. The desired compound 63 (L₂ and R³ asdefined in paragraph [0004]) is purified by crystallization orchromatography.

Step 2—Preparation of Compound 64

Compound 63 in an appropriate solvent (e.g. tetrahydrofuran) under anatmosphere of nitrogen is cooled in an acetone/dry ice bath. To thissolution is added a base (e.g. lithium diisopropylamide) and then anappropriate reagent (e.g. N,N-dimethyl-formamide). The reaction mixtureis stirred for 0.5 to 3 hours at low temperature (<50° C.) and thenallowed to warm to room temperature. The reaction mixture is poured intowater and extracted with an appropriate organic solvent (e.g.dichloromethane or ethyl acetate). The desired compound 64 is purifiedby chromatography.

Step 3—Synthesis of Compound of Formula I where L₁ is —CH₂NR¹¹—

To a mixture of compound 64 in an appropriate organic solvent (e.g.acetonitrile) is added amine 6 (Ar, m, R¹ and R¹¹ as defined inparagraph [0005]), and reducing agent (e.g. triethylsilane andtrifluoroacetic acid). The reaction mixture is heated in an oil bath for2-24 hours. The reaction mixture is concentrated, poured into water andthen extracted with an appropriate organic solvent (e.g. dichloromethaneor ethyl acetate). The organic layers are then combined. The desiredcompound of Formula I is purified by chromatography.

Alternatively, compounds of Formula I where L₁ is —CH₂NR¹¹— may beprepared by reduction of compounds of Formula Ib or Id wherein A is—C(O)— (e.g. prepared as described in Example 1) with an appropriatereducing agent (e.g. borane or diisobutylaluminum hydride).

Example 4: Synthesis of6-chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(propane-1-sulfonylamino)-benzamideP-0011

6-Chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(propane-1-sulfonylamino)-benzamideP-0011 was synthesized in six steps from 4-chloro-2-fluoroaniline 14 asshown in Scheme 4.

Step 1 Preparation 3-Amino-6-Chloro-2-Fluorobenzoic Acid Ethyl Ester(15)

4-Chloro-2-fluoroaniline (14, 12 mL) was dissolved in 200 mL ofanhydrous tetrahydrofuran under a nitrogen atmosphere in a 1 L 3-neckround bottom flask. The mixture was cooled to −78° C. (dry ice/acetonebath) and n-butyllithium (2.5 M, 45 mL) was slowly added dropwise,maintaining the temperature below −70° C. The mixture was stirred at−70° C. for 30 minutes. 1,2-Bis(chlorodimethylsilyl)ethane (24.80 g) wasdissolved in 80 mL of anhydrous tetrahydrofuran and slowly addeddropwise to the reaction mixture while maintaining the temperature below−70° C. The resulting mixture was stirred at −78° C. for 1 hour, thenn-butyllithium (2.5 M, 45 mL) was slowly added dropwise maintaining thetemperature below −70° C. The mixture was then stirred for 30 minutes at−78° C., then warmed up to 15° C. over 1 hour. The reaction mixture wascooled down to −78° C. and n-butyllithium (2.5 M, 50 mL) was slowlyadded dropwise maintaining the temperature below −70° C. The mixture wasstirred at −70° C. for 90 minutes, then 13.40 mL of ethylchloroformatewas slowly added dropwise maintaining the temperature below −70° C. Thereaction mixture was slowly warmed to room temperature and stirred atroom temperature for 64 hours. The reaction was quenched by carefuladdition of a solution of 50 mL of concentrated hydrochloric acid in 160mL of water while cooling with an ice/water bath. The mixture wasstirred at room temperature for 2 hours, then made basic by addition ofpotassium carbonate. The mixture was extracted with 3×100 mL of ethylacetate and the combined organic extracts were washed with 50 mL ofbrine and dried with magnesium sulfate. After removal of the solvent,the residue was purified with silica gel column chromatography elutingwith ethyl acetate in hexane to provide the desired compound (15, 17 g,72%).

Step 2—Preparation 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoicacid ethyl ester (17)

3-Amino-6-chloro-2-fluorobenzoic acid ethyl ester (15, 17 g) wasdissolved in 785 mL of dichloromethane, to which 13.2 mL of pyridine wasadded, followed by propane-1-sulfonylchloride (16, 12.8 g). The reactionmixture was stirred at room temperature for 18 hours, then poured into400 mL of water. The organic layer was separated and the aqueous layerwas extracted with 200 mL of dichlormethane. The combined organicextracts were dried over magnesium sulfate to give an orange oil (41 g).Trituration in 150 mL of diethylether removed the pyridine salt as awhite solid. The ether filtrate was concentrated to give orange oil,which was purified with silica gel column chromatography eluting withethyl acetate in hexane to provide the desired compound as a pale yellowsolid (17, 20 g, 57%).

Step 3 Preparation 6-Chloro-2-Fluoro-3-(Propane-1-Sulfonylamino)-BenzoicAcid (18)

6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid ethyl ester(17, 20 g) was dissolved in a mixture of 500 mL tetrahydrofuran and 150mL water. Lithium hydroxide (12.95 g) was added and the resultingsuspension was stirred at 90° C. for 17 hours. The mixture was cooleddown to room temperature, then brought to pH=1 with concentratedhydrochloric acid (˜36 mL). The aqueous layer was separated andextracted with 3×400 mL of ethyl acetate. The combined organic extractswere dried over magnesium sulfate and concentrated to give a beige solid(25 g). The solid was triturated in 100 mL of diethyl ether for 30minutes, filtered, washed with 50 mL of diethyl ether and dried toprovide the desired compound as a white solid (18, 16 g, 87%).

Step 4—Preparation 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylchloride (19)

6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid 18 wassuspended in anhydrous dichloromethane (30 mL/g). Dimethylformamide (2drops) was added and the suspension cooled in an ice/water bath. Oxalylchloride (5 eq) was slowly added dropwise. The bath was then removed andthe reaction mixture stirred at room temperature for 2 to 3 hours andthe solids slowly disappeared. Dichloromethane and excess oxalylchloride were removed under reduced pressure and the residue was usedwithout further purification in the next step.

Step 5 Preparation ofN-(6-bromo-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide(21)

6-Bromo-pyridin-3-ylamine (20, 3.16 g, 18.26 mmol) was dissolved in 55mL of anhydrous tetrahydrofuran. Triethylamine (1.85 g, 2.55 mL, 18.26mmol) was added and the mixture cooled in an ice/salt bath. A solutionof 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19,3.8 g, 12.17 mmol) in 55 mL of anhydrous tetrahydrofuran was slowlyadded dropwise to the reaction mixture. The resulting mixture wasstirred at room temperature for 18 hours, then diluted with 180 mL ofethyl acetate, washed 2×70 mL with water and once with 110 mL brine,dried over magnesium sulfate and concentrated to give a brown residue.The residue was purified by silica gel flash chromatography, elutingwith 1% methanol, to provide the desired compound as a yellow solid (21,6.9 g, 66%).

Step 6—Preparation6-chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(propane-1-sulfonylamino)-benzamide(P-0011)

N-(6-bromo-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide(21, 250 mg, 0.555 mmol) was placed in a microwave vial along withpalladium acetate (12.5 mg, 0.055 mmol), BINAP (69 mg, 0.111 mmol),potassium tert-butoxide (124 mg, 1.11 mmol) and2-amino-5-methyl-thiazole (22, 190 mg, 1.66 mmol). Dimethylformamide(2.5 mL) was added and the vial sealed. The mixture was then heated at150° C. in a microwave for 3 hours. The black mixture was diluted with50 mL of ethyl acetate and washed with 15 mL of water, then 15 mL of0.67 M hydrochloric acid solution, 15 mL of water and finally 15 mL ofbrine. The organic phase was dried over magnesium sulfate. After removalof the solvent, the residue was purified by preparative TLC and thenHPLC to provide the desired compound as a white solid (P-0011, 10 mg).MS (ESI) [M+H+]⁺=483.8.

Example 5: Synthesis of6-chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamideP-0005

6-Chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamideP-0005 was synthesized in three steps from 2-bromo-5-nitro-pyridine 23as shown in Scheme 5.

Step 1—Preparation of 6-isopropylamino-3-nitro pyridine (25)

2-Bromo-5-nitro-pyridine (23, 400 mg) was placed in a microwave vial.Isopropylamine (24, 3 mL) was added and the vial sealed. The mixture wasthen heated at 120° C. for 30 minutes using a Biotage Initiator EXPmicrowave. The crude mixture was then absorbed on a column and purifiedby silica gel chromatography. The fractions containing the desiredcompound were combined and concentrated to provide the desired compoundas a yellow solid.

Step 2—Preparation of N*2*-isopropyl-pyridine-2,5-diamine (26)

The 6-isopropylamino-3-nitro pyridine 25 was dissolved in methanol (35mL/g). Palladium on carbon catalyst (10%, wet, ˜100 mg) was added andthe suspension was placed under a hydrogen atmosphere at roomtemperature overnight (˜18 hours). The catalyst was removed byfiltration on a pad of celite and washed with 2×10 mL of methanol. Thefiltrate was concentrated under reduced pressure to provide the desiredcompound, which was used without further purification in the next step.

Step 3—Preparation of6-chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamide(P-0005)

N*2*-isopropyl-pyridine-2,5-diamine (26, 155 mg, 1.01 mmol) wasdissolved in 4 mL of anhydrous tetrahydrofuran. Triethylamine (103 mg,142 μL, 1.01 mmol) was added and the mixture cooled in an ice/salt bath.6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19, 200mg, 0.68 mmol) in 4 mL of anhydrous tetrahydrofuran was then slowlyadded dropwise. The resulting mixture was stirred at room temperaturefor 20 hours, then diluted with 30 mL of ethyl acetate, washed with 3×10mL of water and 15 mL of brine. After removal of the solvent, theresidue was purified by silica gel chromatography to provide the desiredcompound as a white solid (P-0005, 35 mg). MS (ESI) [M+H⁺]⁺=429.0.

6-Chloro-N-(6-cyclopentylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0009,6-Chloro-N-(6-cyclopropylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0015,6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-3-yl}-benzamideP-0016, and N-(6-Benzylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0017,

were prepared following the protocol of Scheme 5, replacingisopropylamine 24 with cyclopentylamine, cyclopropylamine,thiophen-2-yl-methylamine and benzylamine, respectively, in Step 1. MS(ESI) [M+H⁺]⁺ P-0009=455.2, P-0015=427.0, P-0016=483.2 and P-0017=477.2.

Example 6: Synthesis ofN-(2-acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0004

N-(2-Acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0004 was synthesized in three steps from 2-amino-5-nitropyrimidine 27as shown in Scheme 6.

Step 1—Preparation of N-(5-nitro-pyrimidin-2-yl)-acetamide (28)

2-Amino-5-nitropyrimidine (27, 500 mg) was suspended in 5 mL of aceticanhydride. The mixture was heated at 160° C. for two hours, then cooledto room temperature. The solids were filtered and washed with 5 mL ofwater, then suspended in 10 mL of water and the pH was brought to 8-9 byaddition of 25% ammonium hydroxide solution. The solids were filtered,washed with 2×10 mL cold water and recrystallized from ethyl acetate toprovide the desired compound as beige needles (28, 382 mg, 58%).

Step 2—Preparation of N-(5-amino-pyrimidin-2-yl)-acetamide (29)

N-(5-Nitro-pyrimidin-2-yl)-acetamide (28, 620 mg) was suspended in 31 mLof methanol. Palladium on carbon catalyst (10%, wet, 60 mg) was addedand the suspension was placed under hydrogen atmosphere for 17 hours.The catalyst was filtered off on a pad of celite and washed with 2×30 mLof methanol. The filtrate was concentrated under reduced pressure toprovide the desired compound as pale yellow needles (29, 520 mg, 100%).

Step 3—Preparation ofN-(2-acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0004

N-(5-amino-pyrimidin-2-yl)-acetamide (29, 154 mg, 1.01 mmol) wasdissolved in 3 mL of anhydrous tetrahydrofuran. Triethylamine (103 mg,142 μL, 1.01 mmol) was added and the mixture cooled in an ice/salt bath.6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19, 200mg, 0.68 mmol) in 3 mL of anhydrous tetrahydrofuran was then slowlyadded dropwise. The resulting mixture was stirred at room temperaturefor 18 hours, then diluted with 20 mL of ethyl acetate, washed with 2×10mL of water and 10 mL of brine. The organic layer was dried overmagnesium sulfate. After removal of the solvent, the residue waspurified by silica gel chromatography to provide the desired compound asa white solid (P-0004, 55 mg, 19%). MS (ESI) [M+H⁺]⁺=430.2.

Example 7: Synthesis ofN-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-benzamideP-0008

N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-benzamideP-0008 was synthesized in three steps from 2,6-difluoro-3-nitro-benzoicacid 30 and N-(5-amino-pyridin-2-yl)-acetamide 31 as shown in Scheme 7.

Step 1—Preparation ofN-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide (32)

2,6-difluoro-3-nitro-benzoic acid (30, 500 mg) was dissolved in 15 mL ofanhydrous dichloromethane. N,N-Dimethylformamide (1 drop) was then addedand the mixture cooled to 5° C. in an ice/water bath. Oxalyl chloride(1.1 mL, 5 eq) was slowly added dropwise. The reaction mixture wasstirred at room temperature for two hours, then concentrated underreduced pressure to give a yellow solid residue, which was dissolved in5 mL of anhydrous tetrahydrofuran and slowly added dropwise to asolution of N-(5-amino-pyridin-2-yl)-acetamide (31, 558 mg, 1.5 eq) andtriethylamine (0.52 mL) in 10 mL of anhydrous tetrahydrofuran. Theresulting suspension was stirred at room temperature overnight. Themixture was diluted with 50 mL of ethyl acetate, washed with 2×25 mL ofwater, then 25 mL brine, dried over magnesium sulfate and concentratedto provide the crude desired compound as a brown solid (32, 980 mg,84%), which was used in the next step without further purification.

Step 2—Preparation ofN-(6-acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide (33)

N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide (32, 950mg) was suspended in 15 mL of methanol. Palladium on carbon catalyst(10%, wet, 100 mg) was added and the suspension was placed underhydrogen atmosphere for 17 hours. The catalyst was filtered off on a padof celite and washed with 2×20 mL of methanol. The filtrate wasconcentrated under reduced pressure to provide the desired compound as ablack solid (33, 750 mg, 86%).

Step 3—Preparation ofN-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-benzamide(P-0008)

N-(6-Acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide (33, 700mg) was dissolved in 35 mL of pyridine. 4-dimethyl-amino-pyridine (1 eq)was added followed by propane-1-sulfonyl chloride (16, 0.80 g, 2.3 eq).The resulting mixture was stirred at room temperature for 3 days, thenat 70° C. for 18 hours. The pyridine was removed under reduced pressureand the residue purified by silica gel column chromatography elutingwith ethyl acetate in hexanes to provide the desired compound as ayellow solid (P-0008, 10 mg, 1%). MS (ESI) [M+H⁺]⁺=412.9.

Additional compounds may be prepared following the protocol of Scheme 7,replacing propane-1-sulfonyl chloride 16 with a suitable sulfonylchloride in Step 3. The following compounds may be prepared by thismethod:

-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-benzamide    (P-0097),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-benzamide    (P-0098),-   N-(6-Acetylamino-pyridin-3-yl)-3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0099),-   N-(6-Acetylamino-pyridin-3-yl)-3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0100),-   N-(6-Acetylamino-pyridin-3-yl)-3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0101),-   6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0102),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzamide    (P-0103),-   N-(6-Acetylamino-pyridin-3-yl)-3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0104),-   N-(6-Acetylamino-pyridin-3-yl)-3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0105),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-benzamide    (P-0106),-   N-(6-Acetylamino-pyridin-3-yl)-3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-benzamide    (P-0107),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-benzamide    (P-0108),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-2-sulfonylamino)-benzamide    (P-0109),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-3-sulfonylamino)-benzamide    (P-0110),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(dimethylaminosulfonylamino)-benzamide    (P-0111),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(piperidine-1-sulfonylamino)-benzamide    (P-0112),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(morpholine-4-sulfonylamino)-benzamide    (P-0113),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-benzamide    (P-0114),-   N-(6-Acetylamino-pyridin-3-yl)-3-cyclopentanesulfonylamino-2,6-difluoro-benzamide    (P-0115),-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-benzamide    (P-0116), and-   N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-benzamide    (P-0117).    The following table indicates the compound number in Column 1, the    sulfonyl chloride used in Step 3 in Column 2, and the resulting    compound in Column 3:

Compound Sulfonyl Chloride in number Step 3 Compound P-0097

P-0098

P-0099

P-0100

P-0101

P-0102

P-0103

P-0104

P-0105

P-0106

P-0107

P-0108

P-0109

P-0110

P-0111

P-0112

P-0113

P-0114

P-0115

P-0116

P-0117

Example 8: Synthesis of pyrrolidine-1-carboxylic acid{5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-yl}-amideP-0006

Pyrrolidine-1-carboxylic acid{5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-yl}-amideP-0006 was synthesized in four steps from 2-amino-5-nitro-pyridine 34 asshown in Scheme 8.

Step 1—Preparation (5-nitro-pyridin-2-yl)-carbamic acid isopropenylester (35)

2-Amino-5-nitro-pyridine (34, 500 mg) was dissolved in 5 mL of anhydroustetrahydrofuran. N-Methyl morpholine (436 mg, 1.2 eq) was added and themixture cooled to −10° C. in an ice/salt acetone bath. A solution ofisopropenyl chloroformate (520 mg) in 5 mL of tetrahydrofuran was thenslowly added dropwise while maintaining the temperature below −10° C.The reaction mixture was stirred at room temperature overnight, thendiluted with 25 mL of ethyl acetate and 20 mL of water. The aqueouslayer was separated and extracted with 2×25 mL of ethyl acetate. Thecombined organic extracts were washed with 25 mL of half saturated brineand dried over magnesium sulfate. After removal of the solvent, theresidue was purified with silica gel column chromatography eluting withethyl acetate in hexane to provide the desired compound as a white solid(35, 0.52 g, 65%).

Step 2—Preparation of pyrrolidine-1-carboxylic acid(5-nitro-pyridin-2-yl)-amide (37)

(5-Nitro-pyridin-2-yl)-carbamic acid isopropenyl ester (35, 160 mg) wasdissolved in 2 mL of anhydrous tetrahydrofuran. N-Methylpyrrolidine (6mg, 0.1 eq) was added, followed by pyrrolidine (36, 51 mg, 1 eq). Themixture was stirred at room temperature overnight, forming aprecipitate. The precipitate was filtered off, washed with 1 mL oftetrahydrofuran and dried to give a white solid. Additional compound wasobtained by concentration of the filtrate under reduced pressure andtrituration of the residue in diethyl ether (˜5 mL) to provide thedesired compound as a beige solid (37, 0.12 g, 71%).

Step 3—Preparation of pyrrolidine-1-carboxylic acid(5-amino-pyridin-2-yl)-amide (38)

Pyrrolidine-1-carboxylic acid (5-nitro-pyridin-2-yl)-amide (37, 115 mg)was dissolved in 10 mL of methanol. Palladium on carbon catalyst wasadded and the suspension placed under a hydrogen atmosphere for 64hours. The catalyst was filtered over a pad of celite and washed with2×10 mL of methanol. The filtrate was concentrated under reducedpressure to provide the desired compound as a grey solid (38, 0.1 g,100%).

Step 4—Preparation of pyrrolidine-1-carboxylic acid{5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-yl}-amide(P-0006)

Pyrrolidine-1-carboxylic acid (5-amino-pyridin-2-yl)-amide (38, 100 mg,0.48 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran.Triethylamine (49 mg, 67 μL, 0.48 mmol) was added and the mixture cooledin an ice/salt bath.6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19, 100mg, 0.34 mmol) in 1 mL of anhydrous tetrahydrofuran was then slowlyadded dropwise. The resulting mixture was stirred at room temperaturefor 60 hours, then diluted with 20 mL of ethyl acetate, washed with 2×10mL of water and 10 mL of brine. The organic layer was dried overmagnesium sulfate. After removal of solvent, the residue was purified bysilica gel column chromatography eluting with ethyl acetate in hexanesto provide the desired compound as a white solid (P-0006, 5 mg, 3%). MS(ESI) [M+H⁺]⁺=484.0.

Example 9: Synthesis of6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamideP-0013

6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamideP-0013 was synthesized in one step from 3-aminoquinoline 39 as shown inScheme 9.

Step 1—Preparation of6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide(P-0013)

3-Aminoquinoline (39, 172 mg, 1.19 mmol) was dissolved in 5 mL ofanhydrous tetrahydrofuran. Triethylamine (120 mg, 170 μL, 1.19 mmol) wasadded and the mixture cooled in an ice/salt bath.6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19, 250mg, 0.80 mmol) in 5 mL of anhydrous tetrahydrofuran was slowly addeddropwise. The resulting mixture was stirred at room temperature for 20hours, then diluted with 30 mL of ethyl acetate, washed with 3×10 mL ofwater and 15 mL of brine. The organic layer was dried over magnesiumsulfate and concentrated to give a pale yellow residue (400 mg), whichwas further triturated in ethyl acetate to provide the desired compoundas a white solid (P-0013, 110 mg, 32%). MS (ESI) [M+H⁺]⁺=421.9.

N-(6-Acetylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0002,6-Chloro-2-fluoro-N-(6-methoxy-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamideP-0003,6-Chloro-N-(3,5-dimethyl-isoxazol-4-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0007,6-chloro-N-[5-(4-chloro-phenyl)-2H-pyrazol-3-yl]-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0010,6-chloro-N-[5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2-fluoro-3-(propane-1-sulfonylamino)-benzamideP-0012,[2-[6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-4H-[1,3,4]thiadiazin-(5E)-ylidene]-aceticacid ethyl ester P-0014, and6-Chloro-2-fluoro-N-imidazo[1,2-a]pyridin-3-yl-3-(propane-1-sulfonylamino)-benzamideP-0018,

were prepared following the protocol of Scheme 9, replacing3-aminoquinoline 39 with N-(5-amino-pyridin-2-yl)-acetamide;6-methoxy-pyridin-3-ylamine; 3,5-dimethyl-isoxazol-4-ylamine;5-(4-chloro-phenyl)-2H-pyrazol-3-ylamine;5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-ylamine;[2-amino-4H-[1,3,4]thiadiazin-(5E)-ylidene]-acetic acid ethyl ester; andimidazo[1,2-a]pyridin-3-ylamine, respectively. MS (ESI) [M+H⁺]⁺P-0002=429.2, P-0003=402.2, P-0007=389.9, P-0010=471.2, P-0012=503.0,P-0014=478.9 and P-0018=411.0.

Example 10: Synthesis of6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamideP-0001

6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamideP-0001 was synthesized in two steps from6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid 18 as shownin Scheme 10.

Step 1—Preparation of6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19)

To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (18, 502mg, 1.70 mmol, prepared as in Step 3 of Scheme 4, Example 4) in 35 mL ofdichloromethane, oxalyl chloride (5 mL, 2.0 M in dichloromethane) andN,N-dimethylformamide (100 μL, 0.001 mol) were added. The reactionmixture was stirred at room temperature for 2 hours. The reaction wasconcentrated to give compound 19, used without further purification.

Step 2—Preparation of6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamide(P-0001)

To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19,0.200 g, 0.64 mmol) in 10.0 mL of dichloromethane, pyridin-3-ylamine(40, 0.126 g, 1.34 mmol) and 4-dimethylaminopyridine (7.8 mg, 0.064mmol) were added. The reaction was stirred at room temperatureovernight. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified with silica gel column chromatography eluting 5% methanol indichloromethane to provide the desired compound (P-0001, 0.15 g, 63%).MS (ESI) [M+H⁺]⁺=371.1.

Example 11: Synthesis of propane-1-sulfonic acid{2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amideP-0019

Propane-1-sulfonic acid{2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amideP-0019 was synthesized in three steps from 2,4-difluoro-phenylamine 41as shown in Scheme 11.

Step 1—Preparation of propane-1-sulfonic acid(2,4-difluoro-phenyl)-amide (42)

To 2,4-difluoro-phenylamine (41, 3.0 mL, 29.8 mmol) in 50 mL oftetrahydrofuran, triethylamine (9.13 mL, 65.5 mmol) andpropane-1-sulfonyl chloride (16, 2.90 mL, 25.8 mmol) were added under anatmosphere of nitrogen. The reaction was stirred at room temperatureovernight. The reaction was poured into 1 M HCl and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated to providethe desired compound (42, 2.0 g, 28%), which was used without furtherpurification in the next step.

Step 2—Preparation of propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide (43)

To propane-1-sulfonic acid (2,4-difluoro-phenyl)-amide (42, 1.5 g, 6.38mmol) in 10 mL of tetrahydrofuran under an atmosphere of nitrogen,cooled in a −78° C. acetone/dry ice bath, lithium diisopropylamide (0.80M in tetrahydrofuran, 24 mL, freshly prepared from n-butyllithium anddiisopropylamine) was added. After 30 minutes, N,N-dimethyl-formamide(542 μL, 7.018 mmol) was added dropwise to the reaction. The reactionwas stirred for 30 minutes at −78° C. and then allowed to warm to roomtemperature for 40 minutes. The reaction was poured into water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 5% ethyl acetate in hexane to give a light yellow solid (43, 300mg, 18%). MS(ESI)[M−H⁺]⁻=262.3.

Step 3—Preparation of propane-1-sulfonic acid{2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amide(P-0019)

To 5-methyl-isoxazol-3-ylamine (44, 0.13 g, 1.3 mmol) in 20 mL ofacetonitrile, propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide (43, 0.35 g, 1.3 mmol),triethylsilane (1 mL, 7 mmol) and trifluoroacetic acid (0.5 mL, 7 mmol)were added. The reaction mixture was stirred at 80° C. overnight. Thereaction mixture was concentrated, then poured into aqueous potassiumcarbonate and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate. After removal of drying agent and thensolvent, the residue was purified by silica gel column chromatography toprovide the desired compound as a white solid (P-0019, 0.22 g, 48%). MS(ESI) [M−H⁺]=346.95.

N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzylamino]-pyridin-2-yl}-acetamideP-0020, propane-1-sulfonic acid[2,4-difluoro-3-(quinolin-3-ylaminomethyl)-phenyl]-amide P-0021,propane-1-sulfonic acid{3-[(6-chloro-pyridin-3-ylamino)-methyl]-2,4-difluoro-phenyl}-amideP-0022, and propane-1-sulfonic acid{2,4-difluoro-3-[(6-methoxy-pyridin-3-ylamino)-methyl]-phenyl}-amideP-0023,

were prepared following the protocol of Scheme 11, replacing5-methyl-isoxazol-3-ylamine 44 with N-(5-amino-pyridin-2-yl)-acetamide,quinolin-3-ylamine, 6-chloro-pyridin-3-ylamine, and6-methoxy-pyridin-3-ylamine, respectively. MS (ESI) [M+H⁺]⁺P-0020=399.35, P-0021=392.40, P-0022=376.95, and P-0023=372.55.

Example 12: Synthesis of quinoline-3-carboxylic acid[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide P-0024 andpropane-1-sulfonic acid{2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide P-0025

Quinoline-3-carboxylic acid[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide P-0024 andpropane-1-sulfonic acid{2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide P-0025 weresynthesized in three steps from propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 43 as shown in Scheme 12.

Step 1—Preparation of 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoicacid (45)

To a reaction flask, propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide (43, 3.00 g, 11.4 mmol) and oxone(9.10 g, 14.8 mmol) and 30 mL of anhydrous N,N-dimethylformamide wereadded under nitrogen. The mixture was stirred at room temperatureovernight, then quenched with 250 mL of 1 M hydrochloric acid solutionand extracted with 250 mL of ethyl acetate. The organic layers werewashed with 3×100 mL of 1M hydrochloric acid solution and dried overmagnesium sulfate. After removal of drying agent and solvent, theresidue was dried in vacuo to provide the desired compound (45, 2.9 g,91%).

Step 2—Preparation of propane-1-sulfonic acid(3-amino-2,4-difluoro-phenyl)-amide (46)

To a reaction flask, 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoicacid (45, 2.88 g, 10.3 mmol), triethylamine (2.09 g, 20.6 mmol) anddiphenylphosphoryl azide (3.21 g, 11.7 mmol) and 84 mL of anhydroustert-butanol were added under nitrogen. The reaction mixture was heatedin an oil bath at 105° C. overnight, then cooled to room temperature anddiluted with ethyl acetate. The organic layer was washed with 3×250 mLof water, 250 mL of brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to provide 4.1 g of crude Boc-protected amine,which was purified by silica gel column chromatography using hexane:ethyl acetate as eluant to provide 3.3 g of the Boc-protected amine.This was dissolved in 50 mL of dichloromethane and 16 mL oftrifluoroacetic acid was added and the reaction stirred at roomtemperature until there was no starting material by TLC. The reactionwas neutralized by pouring into a cooled saturated solution of sodiumbicarbonate and extracted into 3×150 mL of dichloromethane. The combinedorganic extracts were washed with 50 mL of brine, dried over magnesiumsulfate, filtered and concentrated in vacuo to provide the desiredcompound (46, 1.94 g, 75%).

Step 3a—Preparation of quinoline-3-carboxylic acid[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0024)

To a reaction vessel, 3-quinoline carboxylic acid (47, 39.1 mg, 0.23mmol), 1.5 mL of anhydrous tetrahydrofuran, 1 drop of anhydrousN,N-dimethylformamide and oxalyl chloride (86 mg, 0.68 mmol) were addedunder nitrogen. The reaction was stirred at room temperature for 1.5hours, then concentrated to dryness and the residue was diluted with 2mL of anhydrous tetrahydrofuran. To this solution, triethylamine (15.8mg, 0.16 mmol) and propane-1-sulfonic acid(3-amino-2,4-difluoro-phenyl)-amide (46, 100 mg, 0.40 mmol) were addedand the reaction was stirred at room temperature over weekend. Thereaction mixture was diluted with 5 mL of water and extracted into 3×10mL of ethyl acetate. The organic extracts were dried over magnesiumsulfate, filtered and concentrated in vacuo, then purified by silica gelcolumn chromatography (hexane:ethyl acetate gradient) to provide thedesired compound (P-0024, 33 mg, 36%). MS (ESI) [M+H⁺]⁺=406.1.

Step 3b—Preparation of propane-1-sulfonic acid{2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide (P-0025)

To a reaction vessel, propane-1-sulfonic acid(3-amino-2,4-difluoro-phenyl)-amide (46, 155 mg, 0.62 mmol), 2 mL ofanhydrous acetonitrile, 3-quinoline carboxaldehyde (48, 100 mg, 0.64mmol), trifluoroacetic acid (431 mg, 3.78 mmol) and triethylsilane (425mg, 3.65 mmol) were added under nitrogen. The reaction was heated at 80°C. overnight, then cooled to room temperature and concentrated in vacuo,to which 10 mL of an aqueous solution of 10% potassium carbonate wasadded. This was extracted into 3×15 mL of ethyl acetate. The combinedorganic extracts were washed with 15 mL of brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate gradient) toprovide the desired compound (P-0025, 70 mg, 29%). MS (ESI)[M+H⁺]⁺=392.0.

Example 13: Synthesis of propane-1-sulfonic acid[2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide P-0026

Propane-1-sulfonic acid[2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide P-0026 wassynthesized in three steps from propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 43 as shown in Scheme 13.

Step 1—Preparation of propane-1-sulfonic acid(2,4-difluoro-3-hydroxymethyl-phenyl)-amide (49)

To a reaction vessel, propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide (43, 1.00 g, 3.80 mmol), 20 mL ofmethanol, and sodium borohydride (0.29 g, 7.60 mmol) were added undernitrogen. The reaction was stirred at room temperature for 1 hour, thenpoured onto 50 mL of aqueous 10% sodium dihydrogenphosphate. The mixturewas extracted with 3×50 mL of dichloromethane and the combined organicextracts were dried over magnesium sulfate, filtered and concentrated invacuo to provide the desired compound (49, 0.97 g, 96%), used in thenext step without further purification.

Step 2—Preparation of propane-1-sulfonic acid(3-bromomethyl-2,4-difluoro-phenyl)-amide (50)

To a reaction vessel under nitrogen containing polymer-supportedtriphenylphosphine (2.45 g, 4.41 mmol) in 5 mL of acetonitrile, bromine(0.70 g, 4.41 mmol) was added, followed by a solution ofpropane-1-sulfonic acid (2,4-difluoro-3-hydroxymethyl-phenyl)-amide (49,0.97 g, 3.67 mmol) in 5 mL of acetonitrile. The reaction mixture wasstirred at 60° C. for approximately 3 hours. The reaction mixture wasfiltered and the polymer washed with 5 mL of ethyl acetate. The filtrateand wash were concentrated in vacuo to provide the desired compound (50,0.91 g, 76%), used in the next step without further purification.

Step 3—Preparation of propane-1-sulfonic acid[2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide (P-0026)

To reaction vessel, 3-hydroxyquinoline (51, 442 mg, 3.05 mmol) and 5 mLof anhydrous N,N-dimethylformamide were added under nitrogen. Sodiumhydride (60% dispersion in mineral oil, 183 mg, 4.57 mmol) was added inportions. The reaction was stirred at room temperature for 30 minutes,then propane-1-sulfonic acid (3-bromomethyl-2,4-difluoro-phenyl)-amide(50, 500 mg, 1.52 mmol) was added and the reaction stirred at roomtemperature overnight. The reaction mixture was neutralized with aceticacid and extracted into 3×20 mL of ethyl acetate. The combined organicextracts were dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(hexane: ethyl acetate gradient), followed by second purification bysilica gel column chromatography to provide the desired compound(P-0026, 50 mg, 8%). MS (ESI) [M+H⁺]⁺=393.0.

Additional compounds may be prepared following the protocol of Scheme13, optionally replacing propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 43 withN-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide(prepared following the protocol of Scheme 11, Example 11, steps 1 and 2using 4-trifluoromethyl-benzenesulfonyl chloride in Step 1 in place ofpropane-1-sulfonyl chloride 16) in Step 1 and 3-hydroxyquinoline 51 witha suitable alcohol in Step 3. The following compounds may be prepared bythis method:

-   N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyloxy]-pyridin-2-yl}-acetamide    (P-0091),-   Propane-1-sulfonic acid    [3-(2-amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-amide    (P-0092),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-amide    (P-0093),-   N-{5-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzyloxy]-pyridin-2-yl}-acetamide    (P-0094),-   N-[3-(2-Amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide    (P-0095), and-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide    (P-0096).    The following table indicates the compound number in Column 1, the    aldehyde used in Step 1 in Column 2, the alcohol used in Step 3 in    Column 3, and the resulting compound in Column 4:

Compound Aldehyde in Alcohol in number Step 1 Step 3 P-0091

P-0092

P-0093

P-0094

P-0095

P-0096

Compound number Compound P-0091

P-0092

P-0093

P-0094

P-0095

P-0096

Example 14: Synthesis of2,6-difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamideP-0027

2,6-Difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamideP-0027 was synthesized in one step from2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid 45 as shown inScheme 14.

Step 1—Preparation of2,6-difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide(P-0027)

To reaction vessel, 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoicacid (45, 250 mg, 0.90 mmol), 5 mL of anhydrous dichloromethane andanhydrous N,N-dimethylformamide (6.54 mg, 0.09 mmol) were added undernitrogen. The reaction mixture was cooled to 0° C. and oxalyl chloride(568 mg, 4.48 mmol) was added dropwise. This was stirred at roomtemperature for 3 hours, then concentrated in vacuo. The residue wasdiluted with 5 mL of anhydrous tetrahydrofuran and triethylamine (136mg, 1.34 mmol) and 3-aminoquinoline (39, 194 mg, 1.34 mmol) were added.The reaction mixture was stirred at room temperature over the weekend,then concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate gradient) to provide thedesired compound (P-0027, 163 mg, 45%). MS (ESI) [M+H⁺]⁺=406.1.

Example 15: Synthesis of Additional Compounds

Additional compounds may be synthesized in six steps according to thefollowing Scheme 15 or in four steps according the following Scheme 16.

Step 1—Preparation of (2,4-difluoro-phenyl)-carbamic acid methyl ester(52)

To 2,4-difluoroaniline 41, potassium carbonate, and water, methylchloroformate 51 is added slowly dropwise. The reaction is stirred at 0°C. and then allowed to come to room temperature. The reaction mixture isextracted with ethyl acetate and washed with diluted HCl (pH=2), twicewith saturated sodium bicarbonate, twice with brine, and dried withmagnesium sulfate. Removal of solvent provides the desired compound as acrude solid.

Step 2—Preparation of 2,6-difluoro-3-methoxycarbonylamino-benzoic acid(53)

To (2,4-difluoro-phenyl)-carbamic acid methyl ester 52 intetrahydrofuran at −78° C., 2.5 eq. of lithium diisopropylamide isadded. After 15 minutes, solid carbon dioxide is added and the reactionis allowed to warm to room temperature. The reaction mixture isextracted with ethyl acetate and washed with diluted HCl (pH=2). Thedesired compound is isolated by silica gel column chromatography.

Step 3—Preparation of (3-amino-2,4-difluoro-phenyl)-carbamic acid methylester (54)

To 2,6-difluoro-3-methoxycarbonylamino-benzoic acid 53, anhydroustert-butanol, and triethylamine, diphenylphosphoryl azide is added. Theaction is heated in an oil bath at 105° C. overnight. The reaction iscooled to room temperature and diluted with ethyl acetate. The organiclayer is washed 3× with water, then 1× with brine, dried over magnesiumsulfate and filtered and concentrated in vacuo to provide crudeBoc-protected amine, which is purified by silica gel columnchromatography. The purified Boc-protected amine is dissolved indichloromethane, trifluoroacetic acid is added and the reaction stirredat room temperature, monitoring by TLC for the disappearance of startingmaterial. The completed reaction is neutralised by pouring into a cooledsaturated solution of sodium hydrogen carbonate and then extracted 3×into dichloromethane. The combined organic extracts are washed withbrine, dried over magnesium sulfate, filtered and concentrated in vacuoto provide the desired compound.

Step 4—Preparation of Compound 56

To a reaction vessel, carboxylic acid 55 (R^(a) is optionallysubstituted heteroaryl), anhydrous tetrahydrofuran, 1 drop anhydrousdimethylformamide, and oxalyl chloride are added under nitrogen. Thereaction mixture is allowed to stir at room temperature for 1.5 hours,then concentrated to dryness. The resulting residue is diluted withanhydrous tetrahydrofuran, then triethylamine and(3-amino-2,4-difluoro-phenyl)-carbamic acid methyl ester 54 are addedand allowed to stir at room temperature overnight. The reaction isdiluted with water extracted 3× into ethyl acetate. The organic extractsare dried over magnesium sulfate, filtered and concentrated in vacuo toprovide the desired compound as a crude solid, which is purified bysilica gel column chromatography (hexane: ethyl acetate gradient).

Step 5—Preparation of Compound 57

To compound 56 in dioxane, an equal volume of 1 N lithium hydroxide isadded. The reaction is allowed to stir at 60° C. and monitored by TLC.When complete, reaction is extracted with 1N aqueous HCl and ethylacetate. The organic layer is dried over anhydrous magnesium sulfate,filtered and volatile solvents removed to provide the desired compoundas a crude solid.

Step 6—Preparation of Compound 59

To compound 57, tetrahydrofuran is added, followed by addition ofcompound 58 (R^(b) is di-alkylamino, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl or optionally substitutedheteroaryl) as a solution in tetrahydrofuran, then adding pyridine. Thereaction vial is allowed to stir at room temperature. After 23 hours,the reaction is poured into water and 1N aqueous HCl and extracted withethyl acetate. The organic layer is washed with brine, dried overanhydrous magnesium sulfate and filtered. The filtrate is concentratedand purified by silica gel column chromatography (hexane: ethyl acetategradient) to provide the desired compound.

Step 1—Preparation of 2,6-difluoro-3-nitro-phenylamine (61)

2,6-Difluoro-3-nitrobenzoic acid 60 is converted to2,6-difluoro-3-nitro-phenylamine 61 following the methods described inScheme 15, Step 3.

Step 2—Preparation of Compound 62

2,6-Difluoro-3-nitro-phenylamine 61 is reacted with compound 55following the methods described in Scheme 15, Step 4 to provide thedesired compound 62.

Step 3—Preparation of Compound 57

To compound 62 in ethanol and tetrahydrofuran, ˜3 cc of raney nickleslurry in water is added. The reaction is placed in a parr hydrogenatorunder hydrogen at 35 psi and monitored by TLC until all startingmaterial is consumed. The reaction is filtered and all volatile solventsare removed to provide the desired compound as a crude solid.

Step 4—Preparation of Compound 59

Compound 57 is reacted with compound 58 following the methods describedin Scheme 15, Step 6 to provide the desired compound 59.

The following compounds may be made following the protocol of eitherScheme 15 or Scheme 16:

-   6-Acetylamino-N-[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0028),-   6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0029),-   6-Acetylamino-N-[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0030),-   6-Acetylamino-N-[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0031),-   6-Acetylamino-N-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0032),-   6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0033),-   6-Acetylamino-N-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0034),-   6-Acetylamino-N-[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0035),-   6-Acetylamino-N-[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0036),-   6-Acetylamino-N-[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0037),-   6-Acetylamino-N-[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide    (P-0038),-   6-Acetylamino-N-[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-nicotinamide    (P-0039),-   6-Acetylamino-N-[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-nicotinamide    (P-0040),-   6-Acetylamino-N-[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-nicotinamide    (P-0041),-   6-Acetylamino-N-[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-nicotinamide    (P-0042),-   6-Acetylamino-N-[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-nicotinamide    (P-0043),-   6-Acetylamino-N-[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-nicotinamide    (P-0044),-   6-Acetylamino-N-[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-nicotinamide    (P-0045),-   6-Acetylamino-N-(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-nicotinamide    (P-0046),-   6-Acetylamino-N-[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-nicotinamide    (P-0047),-   6-Acetylamino-N-[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-nicotinamide    (P-0048),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide    (P-0049),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide    (P-0050),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0051),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0052),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0053),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide    (P-0054),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide    (P-0055),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0056),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0057),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide    (P-0058),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0059),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide    (P-0060),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-0061),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-0062),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide (P-0063),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide (P-0064),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide (P-0065),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide    (P-0066),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    (3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-0067),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide    (P-0068),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide    (P-0069),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide    (P-0070),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide    (P-0071),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0072),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0073),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0074),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide    (P-0075),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide    (P-0076),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0077),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0078),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide    (P-0079),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide    (P-0080),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide    (P-0081),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-0082),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-0083),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide (P-0084),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide (P-0085),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide (P-0086),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide    (P-0087),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    (3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-0088),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide    (P-0089),-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide    (P-0090),-   6-Acetylamino-N-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-nicotinamide    (P-0118),-   1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid    [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0119),    and-   3H-Imidazo[4,5-b]pyridine-6-carboxylic acid    [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0120).

These compounds are shown in the following table, where column 1provides the compound number, column 2 the carboxylic acid compound 55used in either Step 4 of Scheme 15 or Step 2 of Scheme 16, column 3 thesulfonyl chloride compound 58 used in either Step 6 of Scheme 15 or Step4 of Scheme 16, and column 4 the resulting compound 59.

Compound number Compound 55 Compound 58 P-0028

P-0029

P-0030

P-0031

P-0032

P-0033

P-0034

P-0035

P-0036

P-0037

P-0038

P-0039

P-0040

P-0041

P-0042

P-0043

P-0044

P-0045

P-0046

P-0047

P-0048

P-0118

P-0049

P-0050

P-0051

P-0052

P-0053

P-0054

P-0055

P-0056

P-0057

P-0058

P-0059

P-0060

P-0061

P-0062

P-0063

P-0064

P-0065

P-0066

P-0067

P-0068

P-0069

P-0119

P-0070

P-0071

P-0072

P-0073

P-0074

P-0075

P-0076

P-0077

P-0078

P-0079

P-0080

P-0081

P-0082

P-0083

P-0084

P-0085

P-0086

P-0087

P-0088

P-0089

P-0090

P-0120

Compound number Resulting Compound 59 P-0028

P-0029

P-0030

P-0031

P-0032

P-0033

P-0034

P-0035

P-0036

P-0037

P-0038

P-0039

P-0040

P-0041

P-0042

P-0043

P-0044

P-0045

P-0046

P-0047

P-0048

P-0118

P-0049

P-0050

P-0051

P-0052

P-0053

P-0054

P-0055

P-0056

P-0057

P-0058

P-0059

P-0060

P-0061

P-0062

P-0063

P-0064

P-0065

P-0066

P-0067

P-0068

P-0069

P-0119

P-0070

P-0071

P-0072

P-0073

P-0074

P-0075

P-0076

P-0077

P-0078

P-0079

P-0080

P-0081

P-0082

P-0083

P-0084

P-0085

P-0086

P-0087

P-0088

P-0089

P-0090

P-0120

Example 12: Kinase Activity Assays

Assays for the activity of kinases, including, but not limited to, Fms,Kit, B-Raf, B-Raf V600E, B-Raf V600E/T529I and c-Raf-1 are known in theart, for example as described in US Patent Publication NumberUS20070032519 and U.S. patent application Ser. No. 11/473,347 (see also,PCT publication WO2007002433), the disclosures of which are herebyincorporated by reference in their entireties including allspecifications, figures, and tables, and for all purposes.

Representative compounds screened by at least one of the methodsdescribed above, or by similar methods, having IC₅₀ of less than 10 μMunder the test conditions employed are shown in tables 2a (A-Raf), 2b(B-Raf), 2c (B-Raf V600E), 2d (c-Raf-1), 2e (Brk), 2f (Btk), 2 g (Csk),2h (Fak), 2i (Fms), 2j (Kdr), 2k (Kit), 2i (Lck), 2m (Lyn), 2n (Src), 2o(TrkA), and 2p (Yes).

TABLE 2a Representative compounds with activity toward kinase A-Raf withIC₅₀ ≤ 10 μM under the test conditions employed. A-Raf P-0001, P-0002,P-0004, P-0005, P-0006, P-0008, P-0009, P-0010, P-0011, P-0012, P-0013,P-0015, P-0016, P-0017, P-0020, P-0021, P-0025, P-0026, P-0027

TABLE 2b Representative compounds with activity toward kinase B-Raf withIC₅₀ ≤ 10 μM under the test conditions employed. B-Raf P-0002, P-0004,P-0008, P-0011, P-0013, P-0015, P-0016, P-0017, P-0018, P-0027

TABLE 2c Representative compounds with activity toward kinase B-RafV600E with IC₅₀ ≤ 10 μM under the test conditions employed. B-RafP-0001, P-0002, P-0004, P-0005, P-0008, V600E P-0011, P-0013, P-0015,P-0016, P-0017, P-0018, P-0020, P-0021, P-0025, P-0026, P-0027

TABLE 2d Representative compounds with activity toward kinase c-Raf-1with IC₅₀ ≤ 10 μM under the test conditions employed. c-Raf-1: P-0001,P-0002, P-0004, P-0008, P-0009, P-0011, P-0013, P-0015, P-0016, P-0017,P-0020, P-0021, P-0027

TABLE 2e Representative compounds with activity toward kinase Brk withIC₅₀ ≤ 10 μM under the test conditions employed. Brk: P-0002

TABLE 2f Representative compounds with activity toward kinase Btk withIC₅₀ ≤ 10 μM under the test conditions employed. Btk: P-0011

TABLE 2g Representative compounds with activity toward kinase Csk withIC₅₀ ≤ 10 μM under the test conditions employed. Csk: P-0002

TABLE 2h Representative compounds with activity toward kinase Fak withIC₅₀ ≤ 10 μM under the test conditions employed. Fak: P-0002

TABLE 2i Representative compounds with activity toward kinase Fms withIC₅₀ ≤ 10 μM under the test conditions employed. Fms: P-0010, P-0026

TABLE 2j Representative compounds with activity toward kinase Kdr withIC₅₀ ≤ 10 μM under the test conditions employed. Kdr: P-0011

TABLE 2k Representative compounds with activity toward kinase Kit withIC₅₀ ≤ 10 μM under the test conditions employed. Kit: P-0011

TABLE 2l Representative compounds with activity toward kinase Lck withIC₅₀ ≤ 10 μM under the test conditions employed. Lck: P-0002

TABLE 2m Representative compounds with activity toward kinase Lyn withIC₅₀ ≤ 10 μM under the test conditions employed. Lyn: P-0002

TABLE 2n Representative compounds with activity toward kinase Src withIC₅₀ ≤ 10 μM under the test conditions employed. Src: P-0002, P-0011

TABLE 2o Representative compounds with activity toward kinase TrkA withIC₅₀ ≤ 10 μM under the test conditions employed. TrkA: P-0002, P-0011

TABLE 2p Representative compounds with activity toward kinase Yes withIC₅₀ ≤ 10 μM under the test conditions employed. Yes: P-0002

Example 13: Efficacy of Compounds in Combination with Standard-of-CareChemotherapeutic Agents in Four Human Cancer Cell Lines

Compounds of the invention, such as compounds of Formula I, incombination with a standard chemotherapeutic agent, such as5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,paclitaxel, SN-38, temozolomide, or vinblastine, can be assessed fortheir effectiveness in killing human tumor cells. Such assays are knownin the art, for example, as described in U.S. patent application Ser.No. 11/473,347.

Additional examples of certain methods contemplated by the presentinvention may be found in the following applications: U.S. Patent Publ.No. 2006/058339; U.S. Patent Publ. No. 2006/058340; U.S. Patent Publ.No. 2007/0032519; and U.S. patent application Ser. No. 11/473,347, filedJun. 21, 2006 (Equivalent to PCT published as WO 2007/002433), each ofwhich are hereby incorporated by reference herein in their entiretiesincluding all specifications, figures, and tables, and for all purposes.

All patents and other references cited in the specification areindicative of the level of skill of those skilled in the art to whichthe invention pertains, and are incorporated by reference in theirentireties, including any tables and figures, to the same extent as ifeach reference had been incorporated by reference in its entiretyindividually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims.

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. Thus, for an embodiment of the invention using one of the terms,the invention also includes another embodiment wherein one of theseterms is replaced with another of these terms. In each embodiment, theterms have their established meaning. Thus, for example, one embodimentmay encompass a method “comprising” a series of steps, anotherembodiment would encompass a method “consisting essentially of” the samesteps, and a third embodiment would encompass a method “consisting of”the same steps. The terms and expressions which have been employed areused as terms of description and not of limitation, and there is nointention that in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any 2 different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

Thus, additional embodiments are within the scope of the invention andwithin the following claims.

What is claimed is:
 1. A method for treating a subject with melanoma,thyroid cancer, or colorectal cancer, said method comprisingadministering to the subject: an effective amount of a compound offormula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: L₁ is a bond or—N(H)C(O)—; each R¹ is —N(R⁵)—C(X)—R⁷, lower alkyl, or optionallysubstituted heteroaryl; R² is hydrogen or halogen; R⁴ is hydrogen; R³ isoptionally substituted lower alkyl or optionally substituted aryl; m is0, 1, 2, or 3; Ar is a monocyclic heteroaryl containing 5 to 6 atomswherein at least one atom is nitrogen; R⁵ is hydrogen; X is O; and R⁷ islower alkyl.
 2. The method of claim 1, wherein R² is hydrogen.
 3. Themethod of claim 1, wherein R² is halogen.
 4. The method of claim 1,wherein R³ is optionally substituted phenyl.
 5. The method of claim 1,wherein R³ is phenyl substituted with one or more substituents selectedfrom the group consisting of fluoro, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, and fluoro substituted lower alkylthio.
 6. The method ofclaim 1, wherein R³ is phenyl substituted with one or more fluoro. 7.The method of claim 1, wherein one of the R¹ substituents is lower alkylcontaining 1-4 carbon atoms.
 8. The method of claim 1, wherein one ofthe R¹ substituents is optionally substituted heteroaryl.
 9. The methodof claim 1, further comprising administering a chemotherapeutic agent incombination with the compound of formula (Ia).
 10. The method of claim6, further comprising administering a chemotherapeutic agent incombination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.
 11. The method of claim 7,further comprising administering a chemotherapeutic agent in combinationwith the compound of formula (Ia), and wherein the chemotherapeuticagent is a kinase inhibitor.
 12. The method of claim 8, furthercomprising administering a chemotherapeutic agent in combination withthe compound of formula (Ia), and wherein the chemotherapeutic agent isa kinase inhibitor.
 13. The method of claim 10, wherein the subject hasmelanoma.
 14. The method of claim 10, wherein the melanoma is melanomahaving a B-Raf V600E mutation.
 15. A method for treating a subject withmelanoma, thyroid cancer, or colorectal cancer, said method comprisingadministering to the subject: an effective amount of a compound offormula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: L₁ is a bond;each R¹ is —N(R⁵)—C(X)—R⁷, lower alkyl, or optionally substitutedheteroaryl; R² is hydrogen or halogen; R⁴ is hydrogen; R³ is optionallysubstituted lower alkyl or optionally substituted aryl; m is 0, 1, 2, or3; Ar is a monocyclic heteroaryl containing 5 to 6 atoms wherein atleast one atom is nitrogen; R⁵ is hydrogen; X is O; and R⁷ is loweralkyl.
 16. The method of claim 15, wherein R² is hydrogen.
 17. Themethod of claim 15, wherein R² is halogen.
 18. The method of claim 15,wherein R³ is optionally substituted phenyl.
 19. The method of claim 15,wherein R³ is phenyl substituted with one or more substituents selectedfrom the group consisting of fluoro, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, and fluoro substituted lower alkylthio.
 20. The method ofclaim 15, wherein R³ is phenyl substituted with one or more fluoro. 21.The method of claim 15, wherein one of the R¹ substituents is loweralkyl containing 1-4 carbon atoms.
 22. The method of claim 15, whereinone of the R¹ substituents is optionally substituted heteroaryl.
 23. Themethod of claim 15, further comprising administering a chemotherapeuticagent in combination with the compound of formula (Ia).
 24. The methodof claim 20, further comprising administering a chemotherapeutic agentin combination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.
 25. The method of claim21, further comprising administering a chemotherapeutic agent incombination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.
 26. The method of claim22, further comprising administering a chemotherapeutic agent incombination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.
 27. The method of claim24, wherein the subject has melanoma.
 28. The method of claim 24,wherein the melanoma is melanoma having a B-Raf V600E mutation.
 29. Amethod for treating a subject with non-small cell lung cancer, saidmethod comprising administering to the subject: an effective amount of acompound of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: L₁ is a bond or—N(H)C(O)—; each R¹ is —N(R⁵)—C(X)—R⁷, lower alkyl, or optionallysubstituted heteroaryl; R² is hydrogen or halogen; R⁴ is hydrogen; R³ isoptionally substituted lower alkyl or optionally substituted aryl; m is0, 1, 2, or 3; Ar is a monocyclic heteroaryl containing 5 to 6 atomswherein at least one atom is nitrogen; R⁵ is hydrogen; X is O; and R⁷ islower alkyl.
 30. The method of claim 29, wherein R² is hydrogen.
 31. Themethod of claim 29, wherein R² is halogen.
 32. The method of claim 29,wherein R³ is optionally substituted phenyl.
 33. The method of claim 29,wherein R³ is phenyl substituted with one or more substituents selectedfrom the group consisting of fluoro, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, and fluoro substituted lower alkylthio.
 34. The method ofclaim 29, wherein R³ is phenyl substituted with one or more fluoro. 35.The method of claim 29, wherein one of the R¹ substituents is loweralkyl containing 1-4 carbon atoms.
 36. The method of claim 29, whereinone of the R¹ substituents is optionally substituted heteroaryl.
 37. Themethod of claim 29, further comprising administering a chemotherapeuticagent in combination with the compound of formula (Ia).
 38. The methodof claim 34, further comprising administering a chemotherapeutic agentin combination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.
 39. The method of claim35, further comprising administering a chemotherapeutic agent incombination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.
 40. The method of claim36, further comprising administering a chemotherapeutic agent incombination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.
 41. A method for treatinga subject with non-small cell lung cancer, said method comprisingadministering to the subject: an effective amount of a compound offormula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: L₁ is a bond;each R¹ is —N(R⁵)—C(X)—R⁷, lower alkyl, or optionally substitutedheteroaryl; R² is hydrogen or halogen; R⁴ is hydrogen; R³ is optionallysubstituted lower alkyl or optionally substituted aryl; m is 0, 1, 2, or3; Ar is a monocyclic heteroaryl containing 5 to 6 atoms wherein atleast one atom is nitrogen; R⁵ is hydrogen; X is O; and R⁷ is loweralkyl.
 42. The method of claim 41, wherein R² is hydrogen.
 43. Themethod of claim 41, wherein R² is halogen.
 44. The method of claim 41,wherein R³ is optionally substituted phenyl.
 45. The method of claim 41,wherein R³ is phenyl substituted with one or more substituents selectedfrom the group consisting of fluoro, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, and fluoro substituted lower alkylthio.
 46. The method ofclaim 41, wherein R³ is phenyl substituted with one or more fluoro. 47.The method of claim 41, wherein one of the R¹ substituents is loweralkyl containing 1-4 carbon atoms.
 48. The method of claim 41, whereinone of the R¹ substituents is optionally substituted heteroaryl.
 49. Themethod of claim 41, further comprising administering a chemotherapeuticagent in combination with the compound of formula (Ia).
 50. The methodof claim 46, further comprising administering a chemotherapeutic agentin combination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.
 51. The method of claim47, further comprising administering a chemotherapeutic agent incombination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.
 52. The method of claim48, further comprising administering a chemotherapeutic agent incombination with the compound of formula (Ia), and wherein thechemotherapeutic agent is a kinase inhibitor.